Metalloproteinase inhibitors

ABSTRACT

Compounds of the formula (I) wherein z is SO 2  or SO, useful as metalloproteinase inhibitors, especially as inhibitors of MMP12.

[0001] The present invention relates to compounds useful in theinhibition of metalloproteinases and in particular to pharmaceuticalcompositions comprising these, as well as their use.

[0002] The compounds of this invention are inhibitors of one or moremetalloproteinase enzymes. Metalloproteinases are a superfamily ofproteinases (enzymes) whose numbers in recent years have increaseddramatically. Based on structural and functional considerations theseenzymes have been classified into families and subfamilies as describedin N. M. Hooper (1994) FEBS Letters 354:1-6. Examples ofmetalloproteinases include the matrix metalloproteinases (MMPs) such asthe collagenases (MMP 1, MMP8, MMP13), the gelatinases (MMP2, MMP9), thestromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase(MMP 12), enamelysin (MMP 19), the MT-MMPs (MMP 14, MMP 15, MMP 16, MMP17); the reprolysin or adamalysin or MDC family which includes thesecretases and sheddases such as TNF converting enzymes (ADAM10 andTACE); the astacin family which include enzymes such as procollagenprocessing proteinase (PCP); and other metalloproteinases such asaggrecanase, the endothelin converting enzyme family and the angiotensinconverting enzyme family.

[0003] Metalloproteinases are believed to be important in a plethora ofphysiological disease processes that involve tissue remodelling such asembryonic development, bone formation and uterine remodelling duringmenstruation. This is based on the ability of the metalloproteinases tocleave a broad range of matrix substrates such as collagen, proteoglycanand fibronectin. Metalloproteinases are also believed to be important inthe processing, or secretion, of biological important cell mediators,such as tumour necrosis factor (TNF); and the post translationalproteolysis processing, or shedding, of biologically important membraneproteins, such as the low affinity IgE receptor CD23 (for a morecomplete list see N. M. Hooper et al., (1997) Biochem J. 321:265-279).

[0004] Metalloproteinases have been associated with many diseases orconditions. Inhibition of the activity of one or more metalloproteinasesmay well be of benefit in these diseases or conditions, for example:various inflammatory and allergic diseases such as, inflammation of thejoint (especially rheumatoid arthritis, osteoarthritis and gout),inflammation of the gastro-intestinal tract (especially inflammatorybowel disease, ulcerative colitis and gastritis), inflammation of theskin (especially psoriasis, eczema, dermatitis); in tumour metastasis orinvasion; in disease associated with uncontrolled degradation of theextracellular matrix such as osteoarthritis; in bone resorptive disease(such as osteoporosis and Paget's disease); in diseases associated withaberrant angiogenesis; the enhanced collagen remodelling associated withdiabetes, periodontal disease (such as gingivitis), corneal ulceration,ulceration of the skin, post-operative conditions (such as colonicanastomosis) and dermal wound healing; demyelinating diseases of thecentral and peripheral nervous systems (such as multiple sclerosis);Alzheimer's disease; extracellular matrix remodelling observed incardiovascular diseases such as restenosis and atheroscelerosis; asthma;rhinitis; and chronic obstructive pulmonary diseases (COPD).

[0005] MMP12, also known as macrophage elastase or metalloelastase, wasinitially cloned in the mouse by Shapiro et al [1992, Journal ofBiological Chemistry 267: 4664] and in man by the same group in 1995.MMP-12 is preferentially expressed in activated macrophages, and hasbeen shown to be secreted from alveolar macrophages from smokers[Shapiro et al, 1993, Journal of Biological Chemistry, 268: 23824] aswell as in foam cells in atherosclerotic lesions [Matsumoto et al, 1998,Am J Pathol 153: 109]. A mouse model of COPD is based on challenge ofmice with cigarette smoke for six months, two cigarettes a day six daysa week. Wildtype mice developed pulmonary emphysema after thistreatment. When MMP12 knock-out mice were tested in this model theydeveloped no significant emphysema, strongly indicating that MMP-12 is akey enzyme in the COPD pathogenesis. The role of MMPs such as MMP12 inCOPD (emphysema and bronchitis) is discussed in Anderson and Shinagawa,1999, Current Opinion in Anti-inflammatory and ImmunomodulatoryInvestigational Drugs 1(1): 29-38. It was recently discovered thatsmoking increases macrophage infiltration and macrophage-derived MMP-12expression in human carotid artery plaques Kangavari [Matetzky S,Fishbein MC et al., Circulation 102:(18), 36-39 Suppl. S, Oct. 31,2000].

[0006] MMP13, or collagenase 3, was initially cloned from a cDNA libraryderived from a breast tumour [J. M. P. Freije et al. (1994) Journal ofBiological Chemistry 269(24): 16766-16773]. PCR-RNA analysis of RNAsfrom a wide range of tissues indicated that MMP13 expression was limitedto breast carcinomas as it was not found in breast fibroadenomas, normalor resting mammary gland, placenta, liver, ovary, uterus, prostate orparotid gland or in breast cancer cell lines (T47-D, MCF-7 and ZR75-1).Subsequent to this observation MMP13 has been detected in transformedepidermal keratinocytes [N. Johansson et al., (1997) Cell Growth Differ.8(2):243-250], squamous cell carcinomas [N. Johansson et al., (1997) Am.J. Pathol. 151(2):499-508] and epidermal tumours [K. Airola et al.,(1997) J.

[0007] Invest. Dermatol. 109(2):225-231]. These results are suggestivethat MMP13 is secreted by transformed epithelial cells and may beinvolved in the extracellular matrix degradation and cell-matrixinteraction associated with metastasis especially as observed ininvasive breast cancer lesions and in malignant epithelia growth in skincarcinogenesis.

[0008] Recent published data implies that MMP 13 plays a role in theturnover of other connective tissues; For instance, consistent with MMP13's substrate specificity and preference for degrading type II collagen[P. G. Mitchell et al., (1996) J. Clin. Invest. 97(3):761-768; V.Knauper et al., (1996) The Biochemical Journal 271:1544-1550], MMP 13has been hypothesised to serve a role during primary ossification andskeletal remodelling [M. Stahle-Backdahl et al., (1997) Lab. Invest.76(5):717-728; N. Johansson et al., (1997) Dev. Dyn. 208(3):387-397], indestructive joint diseases such as rheumatoid and osteo-arthritis [D.Wernicke et al., (1996) J. Rheumatol. 23:590-595; P. G. Mitchell et al.,(1996) J. Clin. Invest. 97(3):761-768; O. Lindy et al., (1997) ArthritisRheum 40(8):1391-1399]; and during the aseptic loosening of hipreplacements [S. lmai et al., (1998) J. Bone Joint Surg. Br.80(4):701-710]. MMP13 has also been implicated in chronic adultperiodontitis as it has been localised to the epithelium of chronicallyinflamed mucosa human gingival tissue [V. J. Uitto et al., (1998) Am. J.Pathol 152(6):1489-1499] and in remodelling of the collagenous matrix inchronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol.109(1):96-101].

[0009] MMP9 (Gelatinase B; 92 kDa Type IV Collagenase; 92 kDaGelatinase) is a secreted protein which was first purified, then clonedand sequenced, in 1989 [S. M. Wilhelm et al s (1989) J. Biol Chem. 264(29): 17213-17221; published erratum in J. Biol Chem. (1990) 265 (36):22570]. A recent review of MMP9 provides an excellent source fordetailed information and references on this protease: T. H. Vu & Z. Werb(1998) (In: Matrix Metalloproteinases. 1998. Edited by W. C. Parks & R.P. Mecham. pp115 -148. Academic Press. ISBN 0-12-545090-7). Thefollowing points are drawn from that review by T. H. Vu & Z. Werb(1998).

[0010] The expression of MMP9 is restricted normally to a few celltypes, including trophoblasts, osteoclasts, neutrophils and macrophages.However, it's expression can be induced in these same cells and in othercell types by several mediators, including exposure of the cells togrowth factors or cytokines. These are the same mediators oftenimplicated in initiating an inflammatory response. As with othersecreted MMPs, MMP9 is released as an inactive Pro-enzyme which issubsequently cleaved to form the enzymatically active enzyme. Theproteases required for this activation in vivo are not known. Thebalance of active MMP9 versus inactive enzyme is further regulated invivo by interaction with TIMP-1 (Tissue Inhibitor of Metalloproteinases-1), a naturally-occurring protein. TIMP-1 binds to the C-terminalregion of MMP9, leading to inhibition of the catalytic domain of MMP9.The balance of induced expression of Pro MMP9, cleavage of Pro- toactive MMP9 and the presence of TIMP-1 combine to determine the amountof catalytically active MMP9 which is present at a local site.Proteolytically active MMP9 attacks substrates which include gelatin,elastin, and native Type IV and Type V collagens; it has no activityagainst native Type I collagen, proteoglycans or laminins.

[0011] There has been a growing body of data implicating roles for MMP9in various physiological and pathological processes. Physiological rolesinclude the invasion of embryonic trophoblasts through the uterineepithelium in the early stages of embryonic implantation; some role inthe growth and development of bones; and migration of inflammatory cellsfrom the vasculature into tissues.

[0012] MMP-9 release, measured using enzyme immunoassay, wassignificantly enhanced in fluids and in AM supernantants from untreatedasthmatics compared with those from other populations [Am. J. Resp. Cell& Mol. Biol., Nov 1997, 17(5):583-591]. Also, increased MMP9 expressionhas been observed in certain other pathological conditions, therebyimplicating MMP9 in disease processes such as COPD, arthritis, tumourmetastasis, Alzheimer's, Multiple Sclerosis, and plaque rupture inatherosclerosis leading to acute coronary conditions such as MyocardialInfarction.

[0013] MMP-8 (collagenase-2, neutrophil collagenase) is a 53 kD enzymeof the matrix metalloproteinase family that is preferentially expressedin neutrophils. Later studies indicate MMP-8 is expressed also in othercells, such as osteoarthritic chondrocytes [Shlopov et al, 1997,Arthritis Rheum, 40:2065]. MMPs produced by neutrophils can cause tissueremodelling, and hence blocking MMP-8 should have a positive effect infibrotic diseases of for instance the lung, and in degradative diseaseslike pulmonary emphysema. MMP-8 was also found to be up-regulated inosteoarthritis, indicating that blocking MMP-8 many also be beneficialin this disease.

[0014] MMP-3 (stromelysin-1) is a 53 kD enzyme of the matrixmetalloproteinase enzyme family. MMP-3 activity has been demonstrated infibroblasts isolated from inflamed gingiva [Uitto V. J. et al, 1981, J.Periodontal Res., 16:417-424], and enzyme levels have been correlated tothe severity of gum disease [Overall C. M. et al, 1987, J. PeriodontalRes., 22:81-88]. MMP-3 is also produced by basal keratinocytes in avariety of chronic ulcers [Saarialho-Kere U. K. et al, 1994, J. Clin.Invest., 94:79-88]. MMP-3 mRNA and protein were detected in basalkeratinocytes adjacent to but distal from the wound edge in whatprobably represents the sites of proliferating epidermis. MMP-3 may thusprevent the epidermis from healing. Several investigators havedemonstrated consistent elevation of MMP-3 in synovial fluids fromrheumatoid and osteoarthritis patients as compared to controls[Walakovits L. A. et al, 1992, Arthritis Rheum., 35:35-42; Zafarullah M.et al, 1993, J. Rheumatol., 20:693-697]. These studies provided thebasis for the belief that an inhibitor of MMP-3 will treat diseasesinvolving disruption of extracellular matrix resulting in inflammationdue to lymphocytic infiltration, or loss of structural integritynecessary for organ function.

[0015] A number of metalloproteinase inhibitors are known (see forexample the review of MMP inhibitors by Beckett R. P. and Whittaker M.,1998, Exp. Opin. Ther. Patents, 8(3):259-282]. Different classes ofcompounds may have different degrees of potency and selectivity forinhibiting various metalloproteinases.

[0016] Whittaker M. et al (1999, Chemical Reviews 99(9):2735-27761review a wide range of known MMP inhibitor compounds. They state that aneffective MMP inhibitor requires a zinc binding group or ZBG (functionalgroup capable of chelating the active site zinc(II) ion), at least onefunctional group which provides a hydrogen bond interaction with theenzyme backbone, and one or more side chains which undergo effective vander Waals interactions with the enzyme subsites. Zinc binding groups inknown MMP inhibitors include carboxylic acid groups, hydroxamic acidgroups, sulfhydryl or mercapto, etc. For example, Whittaker M. et aldiscuss the following MMP inhibitors:

[0017] The above compound entered clinical development. It has amercaptoacyl zinc binding group, a trimethylhydantoinylethyl group atthe P1 position and a leucinyl-tert-butyllglycinyl backbone.

[0018] The above compound has a mercaptoacyl zinc binding group and animide group at the P1 position.

[0019] The above compound was developed for the treatment of arthritis.It has a non-peptidic succinyl hydroxamate zinc binding group and atrimethylhydantoinylethyl group at the P1 position.

[0020] The above compound is a phthalimido derivative that inhibitscollagenases. It has a non-peptidic succinyl hydroxamate zinc bindinggroup and a cyclic imide group at P1. Whittaker M. et al also discussother MMP inhibitors having a P1 cyclic imido group and various zincbinding groups (succinyl hydroxamate, carboxylic acid, thiol group,phosphorous-based group).

[0021] The above compounds appear to be good inhibitors of MMP8 and MMP9(PCT patent applications WO9858925, WO9858915). They have apyrimidin-2,3,4-trione zinc binding group.

[0022] The following compounds are not known as MMP inhibitors:Lora-Tamayo, M et al (1968, An. Quim 64(6): 591-606) describe synthesisof the following compounds as a potential anti-cancer agent:

[0023] Czech patent numbers 151744 (19731119) and 152617 (1974022)describe the synthesis and the anticonvulsive activity of the followingcompounds:

[0024] R=4-NO2, 4-OMe, 2-NO2,

[0025] U.S. Pat. No. 3,529,019 (19700915) describes the followingcompounds used as intermediates:

[0026] PCT patent application number WO 00/09103 describes compoundsuseful for treating a vision disorder, including the following(compounds 81 and 83, Table A, page 47):

[0027] We have now discovered a new class of compounds that areinhibitors of metalloproteinases and are of particular interest ininhibiting MMPs such as MMP-12. The compounds are metalloproteinaseinhibitors having a metal binding group that is not found in knownmetalloproteinase inhibitors. In particular, we have discoveredcompounds that are potent MMP12 inhibitors and have desirable activityprofiles. The compounds of this invention have beneficial potency,selectivity and/or pharmacokinetic properties.

[0028] The metalloproteinase inhibitor compounds of the inventioncomprise a metal binding group and one or more other functional groupsor side chains characterised in that the metal binding group has theformula (k)

[0029] wherein X is selected from NR1, O, S;

[0030] Y1 and Y2 are independently selected from O, S;

[0031] R1 is selected from H, alky, haloalkyl;

[0032] Any alkyl groups outlined above may be straight chain orbranched; any alkyl group outlined above is preferably (C1-7)alkyl andmost preferably (C1-6)alkyl.

[0033] A metalloproteinase inhibitor compound is a compound thatinhibits the activity of a metalloproteinase enzyme (for example, anMMP). By way of non-limiting example the inhibitor compound may showIC50s in vitro in the range of 0. 1-10000 nanomolar, preferably 0.1-1000nanomolar.

[0034] A metal binding group is a functional group capable of bindingthe metal ion within the active site of the enzyme. For example, themetal binding group will be a zinc binding group in MMP inhibitors,binding the active site zinc(II) ion. The metal binding group of formula(k) is based on a five-membered ring structure and is preferably ahydantoin group, most preferably a −5 substituted1-H,3-H-imidazolidine-2,4dione.

[0035] In a first aspect of the invention we now provide compounds ofthe formula I

[0036] wherein

[0037] X is selected from NR1, O, S;

[0038] Y1 and Y2 are independently selected from O, S;

[0039] Z is selected from SO, SO₂;

[0040] m is 1 or 2;

[0041] A is selected from a direct bond, (C1-6)alkyl, (C1-6)haloalkyl,or (C1-6)heteroalkyl containing a hetero group selected from N, O, S,SO, SO₂ or containing two hetero groups selected from N, O, S, SO, SO₂and separated by at least two carbon atoms;

[0042] R1 is selected from H, (C1-3)alkyl, haloalkyl;

[0043] Each R2 and R3 is independently selected from H, halogen(preferably fluorine), alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl,heteroalkyl-heteroaryl, aryl-alkyl, aryl-heteroalkyl, heteroaryl-alkyl,heteroaryl-heteroalkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl,heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl,alkyl-cycloalkyl, alkyl-heterocycloalkyl;

[0044] Each R4 is independently selected from H, halogen (preferablyfluorine), (C1-3)alkyl or haloalkyl;

[0045] Each of the R2 and R3 radicals may be independently optionallysubstituted with one or more (preferably one) groups selected fromalkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy,haloalkoxy, thiol, alkylthiol, arylthiol, alkylsulfon, haloalkylsulfon,arylsulfon, aminosulfon, N-alkylaminosulfon, N,N-dialkylaminosulfon,arylaminosulfon, amino, N-alkylamino, N,N-dialkylamino, amido,N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkylsulfonamino,arylsulfonamino, amidino, N-aminosulfon-amidino, guanidino,N-cyano-guanidino, thioguanidino, 2-nitro-ethene-1,1-diamin, carboxy,alkyl-carboxy, nitro, carbamate;

[0046] Optionally R2 and R3 may join to form a ring comprising up to 7ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ringatoms, or R3 and R4 may join to form a ring comprising up to 7 ringatoms;

[0047] R5 is a monocyclic, bicyclic or tricyclic group comprising one,two or three ring structures each of up to 7 ring atoms independentlyselected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, witheach ring structure being independently optionally substituted by one ormore substituents independently selected from halogen, hydroxy, alkyl,alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino,alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol,alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate,alkylcarboxylate, aminocarboxy, N-alkylamino-carboxy,N,N-dialkylamino-carboxy, wherein any alkyl radical within anysubstituent may itself be optionally substituted with one or more groupsselected from halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino,N,N-dialkylamino, N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro,thiol, alkylthiol, alkylsulfonyl, N-alkylaminosulfonyl, carboxylate,alkylcarboxy, aminocarboxy, N-alkylaminocarboxy,N,N-dialkylaminocarboxy, carbamate,

[0048] when R5 is a bicyclic or tricyclic group, each ring structure isjoined to the next ring structure by a direct bond, by —O—, by(C1-6)alkyl, by (C1-6)haloalkyl, by (C1-6)heteroalkyl, by (C1-6)alkenyl,by (C1-6)alkynyl, by sulfone, by CO, by NCO, by CON, by NH, by Sp byC(OH) or is fused to the next ring structure;

[0049] Any heteroalkyl group outlined above is a hetero atom-substitutedalkyl containing one or more hetero groups independently selected fromN, O, S, SO, SO2, (a hetero group being a hetero atom or group ofatoms);

[0050] Any heterocycloalkyl or heteroaryl group outlined above containsone or more hetero groups independently selected from N, O, S, SO, SO2;

[0051] Any alkyl, alkenyl or alkynyl groups outlined above may bestraight chain or branched; unless otherwise stated, any alkyl groupoutlined above is preferably (C1-7)alkyl and most preferably(C1-6)alkyl.

[0052] Preferred compounds of the formula I are those wherein any one ormore of the following apply:

[0053] X is NR1;

[0054] Z is SO₂ or SO; especially Z is SO₂;

[0055] At least one of Y1 and Y2 is O; especially both Y1 and Y2 are O;

[0056] m is 1;

[0057] R1 is H, (C1-3) alkyl, (C1-3) haloalkyl; especially R1 is H,(C1-3)alkyl; most especially R1 is H;

[0058] R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl,aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl,alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl,alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; especiallyR2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl orheteroaryl-alkyl.

[0059] R3 and/or R4 is H;

[0060] R3 and/or R4 is methyl;

[0061] R5 comprises one, two or three optionally substituted aryl orheteroaryl 5 or 6 membered rings;

[0062] R5 is a bicyclic or tricyclic group comprising two or threeoptionally substituted ring structures.

[0063] Particularly preferred compounds of formula I are those whereinR5 is a bicyclic or tricyclic group comprising two or three optionallysubstituted ring structures.

[0064] The invention further provides compounds of the formula II

[0065] wherein

[0066] each of G1, G2 and G4 is a monocyclic ring structure comprisingeach of up to 7 ring atoms independently selected from cycloalkyl, aryl,heterocycloalkyl or heteroaryl, with each ring structure beingindependently optionally substituted by one or two substituentsindependently selected from halogen, hydroxy, haloalkoxy, amino,N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkylsulfone, haloalkyl sulfone, alkylcarbamate, alylamide, wherein any alkylradical within any substituent may itself be optionally substituted withone or more groups selected from halogen, hydroxy, amino, N-alkylamino,N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy,heteroaryloxy, carbamate;

[0067] Z is SO₂;

[0068] Each of B and F is independently selected from a direct bond, O,(C1-6)alkyl, (C1-6)heteroalkyl, alkynyl, CO, NCO, CON, NH, S;

[0069] R2 is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl,amidoalkyl, thioalkyl cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl,alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl,alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl;

[0070] R3 and R4 are independently selected from H or (C1-3)alkyl,

[0071] Optionally R2 and R3 may join to form a ring comprising up to 7ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ringatoms, or R3 and R4 may join to form a ring comprising up to 7 ringatoms;

[0072] Any heteroalkyl group outlined above is a hetero atom-substitutedalkyl containing one or more hetero groups independently selected fromN, O, S, SO, SO 2, (a hetero group being a hetero atom or group ofatoms);

[0073] Any heterocycloalkyl or heteroaryl group outlined above containsone or more hetero groups independently selected from N, O, S, SO, SO 2;

[0074] Any alkyl, alkenyl or alkynyl groups outlined above may bestraight chain or branched; unless otherwise stated, any alkyl groupoutlined above is preferably (C1-7)alkyl and most preferably(C1-6)alkyl.

[0075] Preferred compounds of the formula II include those wherein R2 isalkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl orheteroaryl-alkyl.

[0076] The invention further provides compounds of the formula IIa

[0077] wherein

[0078] each of G1 and G2 is a monocyclic ring structure comprising eachof up to 7 ring atoms independently selected from cycloalkyl, aryl,heterocycloalkyl or heteroaryl, with each ring structure beingindependently optionally substituted by one or two substituentsindependently selected from halogen, hydroxy, haloalkoxy, amino,N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkylsulfone, haloalkyl sulfone, alkylcarbamate, alkylamide, wherein anyalkyl radical within any substituent may itself be optionallysubstituted with one or more groups selected from halogen, hydroxy,amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy,aryloxy, heteroaryloxy, carbamate;

[0079] Z is SO₂;

[0080] B is selected from a direct bond, O, (C1-6)alkyl,(C1-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl;

[0081] R2 is selected from H, (C1-6)alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl,amidoalkyl, thioalkyl, or R2 is a group of formula III

[0082] C and D are independently selected from a direct bond, H,(C1-C6)alkyl, (C1-C6)haloalkyl, or (C1-C6)heteroalkyl containing one ortwo hetero atoms selected from N, O or S such that when two hetero atomsare present they are separated by at least two carbon atoms;

[0083] G3 is a monocyclic ring structure comprising up to 7 ring atomsindependently selected from cycloalkyl, aryl, heterocycloalkyl orheteroaryl, optionally substituted by one or two substituentsindependently selected from halogen, hydroxy, amino, N-alkylamino,N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkylsulfone, or alkyl substituted with one or more groups selected fromhalogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro,alkoxy, haloalkoxy;

[0084] Optionally R2 is substituted with halo, haloalkyl, hydroxy,alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino,(N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone,aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido,N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino,amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino,thioguanidino, 2-nitroguanidino, carboxy, alkylcarboxy, carbamate;

[0085] R3 and R4 are independently selected from H or (C1-3)alkyl;

[0086] Optionally R2 and R3 may join to form a ring comprising up to 7ring atoms, or R2 and R4 may join to form a ring comprising up to 7 ringatoms, or R3 and R4 may join to form a ring comprising up to 7 ringatoms;

[0087] Any heteroalkyl group outlined above is a hetero atom-substitutedalkyl containing one or more hetero groups independently selected fromN, O, S, SO, SO2, (a hetero group being a hetero atom or group ofatoms);

[0088] Any heterocycloalkyl or heteroaryl group outlined above containsone or more hetero groups independently selected from N, O, S, SO, SO2;

[0089] Any alkyl, alkenyl or alkynyl groups outlined above may bestraight chain or branched; unless otherwise stated, any alkyl groupoutlined above is preferably (C1-7)alkyl and most preferably(C1-6)alkyl.

[0090] Preferred compounds of the formula IIa are those wherein one ormore of the following apply:

[0091] B is selected from a direct bond, O, CO, S, alkynyl; especially Bis a direct bond, O, S, or alkynyl;

[0092] R2 is selected from H, (C1-6)alkyl, aryl-(C1-6)alkyl orheteroaryl-(C1-6)alkyl optionally substituted with halo, haloalkyl,hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino,N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl,alkylsulfone, aminosulfone, N-alkylamino-sulfone,N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido,carbamate, cyano, sulfonamino, alkyl-sulfonamino, amidino,N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino,2-nitroguanidino, 2-nitro-ethene- 1,1-diamino, carboxy, alkylcarboxy,carbamate;

[0093] Each of R3 and R4 is H;

[0094] G2 is a nitrogen containing six-membered ring;

[0095] G1 is para substituted.

[0096] Particularly preferred compounds of formula IIa are those whereineach of R3 and R4 is H.

[0097] For example, particular compounds of the invention includecompounds of formula IIa wherein B is a direct bond, O, S or alkynyl;and R2 is selected from H, (C1 -6)alkyl, aryl-(C1-6)alkyl orheteroaryl-(C1-6)alkyl optionally substituted with cyckloalkyl,heterocycloalkyl, halo, haloalkyl, hydroxy, alkoxy, aryloxy, haloalkoxy,amino, arninoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl,(N,N-dialkylamino)alkyl, alkylsulfonyl, aminosulfonyl,N-alkylamino-sulfonyl, N,N-dialkylamino-sulfonyl, amido, N-alkylamido,N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino,N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino,2-nitroguanidino, carbamate, carboxy, alkylcarboxy; and each of R3 andR4 is H.

[0098] Particularly preferred compounds of the invention are those ofFormula IIb:

[0099] wherein G2 is optionally substituted piperidine or piperazine,and G1, B, and R2 are as described for Formula IIa.

[0100] In a compound of Formula IIb, preferably G2 is unsubstituted andG1 is optionally substituted, preferably G1 is para substituted.Suitable values for R2 include the following:

[0101] Suitable values for R5 include the following:

[0102] It will be appreciated that the particular substituents andnumber of substituents in compounds of the invention are selected so asto avoid sterically undesirable combinations.

[0103] Each exemplified compound represents a particular and independentaspect of the invention.

[0104] Where optically active centres exist in the compounds of theinvention, we disclose all individual optically active. forms andcombinations of these as individual specific embodiments of theinvention, as well as their corresponding racemates. Racemates may beseparated into individual optically active forms using known procedures(cf. Advanced Organic Chemistry: 3rd Edition: author J March, p104-107)including for example the formation of diastereomeric derivatives havingconvenient optically active auxiliary species followed by separation andthen cleavage of the auxiliary species.

[0105] It will be appreciated that the compounds according to theinvention may contain one or more asymmetrically substituted carbonatoms. The presence of one or more of these asymmetric centres (chiralcentres) in a compound of the invention can give rise to stereoisomers,and in each case the invention is to be understood to extend to all suchstereoisomers, including enantiomers and diastereomers, and mixturesincluding racemic mixtures thereof.

[0106] Where tautomers exist in the compounds of the invention, wedisclose all individual tautomeric forms and combinations of these asindividual specific embodiments of the invention.

[0107] As previously outlined the compounds of the invention aremetalloproteinase inhibitors, in particular they are inhibitors ofMMP12. Each of the above indications for the compounds of the theinvention represents an independent and particular embodiment of theinvention.

[0108] Certain compounds of the invention are of particular use asinhibitors of MMP 13 and/or MMP9 and/or MMP8 and/or MMP3.

[0109] Compounds of the invention show a favourable selectivity profile.Whilst we do not wish to be bound by theoretical considerations, thecompounds of the invention are believed to show selective inhibition forany one of the above indications relative to any MMP1 inhibitoryactivity, by way of non-limiting example they may show 100-1000 foldselectivity over any MMP1 inhibitory activity.

[0110] The compounds of the invention may be provided aspharmaceutically acceptable salts. These include acid addition saltssuch as hydrochloride, hydrobromide, citrate and maleate salts and saltsformed with phosphoric and sulphuric acid. In another aspect suitablesalts are base salts such as an alkali metal salt for example sodium orpotassium, an alkaline earth metal salt for example calcium ormagnesium, or organic amine salt for example triethylamine.

[0111] They may also be provided as in vivo hydrolysable esters. Theseare pharmaceutically acceptable esters that hydrolyse in the human bodyto produce the parent compound. Such esters can be identified byadministering, for example intravenously to a test animal, the compoundunder test and subsequently examining the test animal's body fluids.Suitable in vivo hydrolysable esters for carboxy include methoxymethyland for hydroxy include formyl and acetyl, especially acetyl.

[0112] In order to use a metalloproteinase inhibitor compound of theinvention (a compound of the formula I or II, Ia or IIb) or apharmaceutically acceptable salt or in vivo hydrolysable ester thereoffor the therapeutic treatment (including prophylactic treatment) ofmammals including humans, it is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

[0113] Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the invention(a compound of the formula I or II, IIa or IIb) or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester and pharmaceuticallyacceptable carrier.

[0114] The pharmaceutical compositions of this invention may beadministered in standard manner for the disease or condition that it isdesired to treat, for example by oral, topical, parenteral, buccal,nasal, vaginal or rectal adminstration or by inhalation. For thesepurposes the compounds of this invention may be formulated by meansknown in the art into the form of, for example, tablets, capsules,aqueous or oily solutions, suspensions, emulsions, creams, ointments,gels, nasal sprays, suppositories, finely divided powders or aerosolsfor inhalation, and for parenteral use (including intravenous,intramuscular or infusion) sterile aqueous or oily solutions orsuspensions or sterile emulsions.

[0115] In addition to the compounds of the present invention thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseases orconditions referred to hereinabove.

[0116] The pharmaceutical compositions of this invention will normallybe administered to humans so that, for example, a daily dose of 0.5 to75 mg/kg body weight (and preferably of 0.5 to 30 mg/kg body weight) isreceived. This daily dose may be given in divided doses as necessary,the precise amount of the compound received and the route ofadministration depending on the weight, age and sex of the patient beingtreated and on the particular disease or condition being treatedaccording to principles known in the art.

[0117] Typically unit dosage forms will contain about 1 mg to 500 mg ofa compound of this invention.

[0118] Therefore in a further aspect, we provide a compound of theformula I or a pharmaceutically acceptable salt or in vivo hydrolysableester thereof for use in a method of therapeutic treatment of the humanor animal body or for use as a therapeutic agent. We disclose use in thetreatment of a disease or condition mediated by one or moremetalloproteinase enzymes. In particular we disclose use in thetreatment of a disease or condition mediated by MMP12 and/or MMP13and/or MMP9 and/or MMP8 and/or MMP3; especially use in the treatment ofa disease or condition mediated by MMP12 or MMP9; most especially use inthe treatment of a disease or condition mediated by MMP12.

[0119] In particular we provide a compound of the formula II, IIa or IIbor a pharmaceutically acceptable salt or in vivo hydrolysable esterthereof for use in a method of therapeutic treatment of the human oranimal body or for use as a therapeutic agent (such as use in thetreatment of a disease or condition mediated by MMP12 and/or MMP13and/or MMP9 and/or MMP8 and/or MMP3; especially MMP12 or MMP9; mostespecially MMP12).

[0120] In yet a further aspect we provide a method of treating ametalloproteinase mediated disease or condition which comprisesadministering to a warm-blooded animal a therapeutically effectiveamount of a compound of the formula I or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof. We also disclose the use ofa compound of the formula I or a pharmaceutically acceptable salt or invivo hydrolysable precursor thereof in the preparation of a medicamentfor use in the treatment of a disease or condition mediated by one ormore metalloproteinase enzymes.

[0121] For example we provide a method of treating a metalloproteinasemediated disease or condition which comprises administering to awarm-blooded animal a therapeutically effective amount of a compound ofthe formula II, IIa or IIb (or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof). We also provide the use of a compoundof the formula II, IIa or IIb (or a pharmaceutically acceptable salt orin vivo hydrolysable precursor thereof) in the preparation of amedicament for use in the treatment of a disease or condition mediatedby one or more metalloproteinase enzymes.

[0122] Metalloproteinase mediated diseases or conditions include asthma,rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (suchas rheumatoid arthritis and osteoarthritis), atherosclerosis andrestenosis, cancer, invasion and metastasis, diseases involving tissuedestruction, loosening of hip joint replacements, periodontal disease,fibrotic disease, infarction and heart disease, liver and renalfibrosis, endometriosis, diseases related to the weakening of theextracellular matrix, heart failure, aortic aneurysms, CNS relateddiseases such as Alzheimer's disease and Multiple Sclerosis (MS),hematological disorders.

[0123] Preparation of the Compounds of the Invention

[0124] In another aspect the present invention provides a process forpreparing a compound of the formula I or II, IIa, IIb or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as described in (a) to (d) below. It will be appreciated that many ofthe relevant starting materials are commercially or otherwise availableor may be synthesised by known methods or may be found in the scientificliterature.

[0125] (a) Compounds of formula I in which Y1and Y 2 are each O, Z isSO₂, R2 is as defined in formula I, A is a direct bond and R1 comprisesa nitrogen directly attached to Z, or A is (C1-6) N-alkyl, may beprepared by reacting a compound of the formula IV in which R5 is definedas in formula I with the known compounds of the formula V in which X andm are as defined in formhula I:

[0126] The reaction is preferably performed in suitable solventoptionally in the presence of base for 1 to 24 h at ambient to refluxtemperature. Preferably, solvents such as pyridine, dimethylformamide,tetrahydrofurane, acetonitrile or dichlorometane are used with baseslike triethylamine, N-methylmorpholine, pyridine or alkali metalcarbonates at ambient temperature for 2-16 h reaction time, or until endof reaction is achieved as detected by chromatographic or spectroscopicmethods. Reactions of sulfonyl chlorides of formula V with variousprimary and secondary amines are previously described in the literature,and the variations of the conditions will be evident for those skilledin the art.

[0127] Synthesis of compounds of formula V is described in theliterature and can be prepared from e.g. cystein or homocystein (Mosher,J.: J. Org. Chem. 23,1257 (1958). Sulfonylchlorides of formula V, inwhich m=1, X=NR1(R1=H) and R2 is as described in formula I, areconveniently prepared by oxidative chlorination of compounds of formulaVa, in which R2 is as described in formula I (Griffith, O.: J. Biol.Chem., 1983, 258, 3, 1591).

[0128] (b) Compounds of formula I in which Y1 and Y2 are each O, Z is S,and X and R5 are as described in formula I may be prepared by reacting acompound of formula VI in which K is a leaving group (e.g chloride, orsulfonate ester) and R5 as described in formula I,

[0129] with a compound of formula VII, in which G is a sulfhydryl (SH),X and m as described in formula I. The reaction is preferably performedin the presence of base such as diethyl isopropyl amine or cesiumcarbonate and in the presence of a suitable solvent e.g DMF.

[0130] Alternatively, the compounds under process (b) may be prepared inthe same manner as in process (b), by reacting the compounds of formulaVI and VII, but in which K in compound VI is the sulfhydryl (SH) or ahydroxyl group and G in formula VII represents a leaving group.

[0131] (c) Compounds of the formula I in which Y1 and Y2 are each O, Zis SO2 or S(O), and X, A, and R5 are as described in formula I, may beprepared by oxidizing the final products described under process (b) andin which Z is S, with oxidizing agents like peroxide reagents,preferably m-chloroperbenzoic acid or oxone.

[0132] (d) Compounds of the formula I in which Y1 and Y2 are each O, Xis NR1(R1=H), m is 1, and R2, R3, R4, R5 are as described in formula Imay be prepared by reacting a compound of formula XI in which R2, R3,R4, R5 and A are as described in formula I,

[0133] with ammonium and cyanide salts in protic solvents, preferably inthe presence of excess ammonium carbonat and potassium cyanide inethanol in a sealed vessel at 40-80° C. for 4-24 hours.

[0134] The ketones of formula XI are conveniently prepared by treatingsulfonamides of formula XII in which R3 is H and R5 is as described informula I, with excess strong base and then treatment with esters offormula XIII, in which R is an alkyl or aryl residue and R2 are asdescribed for formula I, in non-protic solvents. Preferrable conditionsare 2-3 equivalents of lithium bases like lithium diisopropylamide orlithium hexamethyldisilazane or butyl lithium in dried etheral solventslike tetrahydrofurane.

[0135] The ketones of formula XI, in which R3 and R4 are each alkyl orform a ring, R5 is aryl or heteroaryl and R2 is alkyl or aryl, can alsobe prepared by treating sulfinates of formula XIV in which R5 is aryl orheteroaryl as described in formula I, with a base such astetrabutylammonium bromide and a ketone of formula XV in which R2 isalkyl or aryl (Crandall et al J. Org. Chem. 1985, (8) 50, 1327-1329). R3and R4 are then introduced by reaction with alkyl halides or alkyldihalides. The reaction is preferably performed in the presence of basesuch as potassium carbonate or caesium carbonate and in the presence ofa suitable solvent e.g. DMF or DMSO at 50-100° C.

[0136] The compounds of the invention may be evaluated for example inthe following assays:

[0137] Isolated Enzyme Assays

[0138] Matrix Metallooroteinase family including for example MMP12,MMP13.

[0139] Recombinant human MMP12 catalytic domain may be expressed andpurified as described by Parkar A. A. et al, (2000), Protein Expressionand Purification, 20:152. The purified enzyme can be used to monitorinhibitors of activity as follows: MMP12 (50 ng/ml final concentration)is incubated for 30 minutes at RT in assay buffer (0.1M Tris-HCl, pH 7.3containing 0.1M NaCl, 20 mM CaCl₂, 0.040 mM ZnCl and 0.05% (w/v) Brij35) using the synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 inthe presence or absence of inhibitors. Activity is determined bymeasuring the fluorescence at λex 328 nm and λem 393 nm. Percentinhibition is calculated as follows: % Inhibition is equal to the[Fluorescence_(plus inhibitor)−Fluorescence_(background)] divided by the[Fluorescence_(minus inhibitor)−Fluorescence_(background)].

[0140] Recombinant human proMMP13 may be expressed and purified asdescribed by Knauper et al. [V. Knauper et al., (1996) The BiochemicalJournal 271:1544-1550 (1996)]. The purified enzyme can be used tomonitor inhibitors of activity as follows: purified proMMP13 isactivated using 1 mM amino phenyl mercuric acid (APMA), 20 hours at 21°C.; the activated MMP13 (11.25 ng per assay) is incubated for 4-5 hoursat 35° C. in assay buffer (0.1 M Tris-HCl, pH 7.5 containing 0.1 M NaCl,20 mM CaCl2, 0.02 mM ZnCl and 0.05% (w/v) Brij 35) using the syntheticsubstrate7-methoxycoumarin-4-yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg-NH₂in the presence or absence of inhibitors. Activity is determined bymeasuring the fluorescence at λex 328 nm and λem 393 nm. Percentinhibition is calculated as follows: % Inhibition is equal to the[Fluorescence_(plus inhibitor)−Fluorescence_(background)] divided by the[Fluorescence_(minus inhibitor)−Fluorescence_(background)].

[0141] A similar protocol can be used for other expressed and purifiedpro MMPs using substrates and buffers conditions optimal for theparticular MMP, for instance as described in C. Graham Knight et al.,(1992) FEBS Lett. 296(3):263-266.

[0142] Adamalysin Family Including For Example TNF Convertase

[0143] The ability of the compounds to inhibit proTNFα convertase enzymemay be assessed using a partially purified, isolated enzyme assay, theenzyme being obtained from the membranes of THP-1 as described by K. M.Mohler et al., (1994) Nature 370:218-220. The purified enzyme activityand inhibition thereof is determined by incubating the partiallypurified enzyme in the presence or absence of test compounds using thesubstrate 4′,5′-Dimethoxy-fluoresceinylSer.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-succinimid-1-yl)-fluorescein)-NH₂in assay buffer (50 mM Tris HCl, pH 7.4 containing 0.1% (w/v) TritonX-100 and 2 mM CaCl₂), at 26° C. for 18 hours. The amount of inhibitionis determined as for MMP13 except λex 490 nm and λem 530 nm were used.The substrate was synthesised as follows. The peptidic part of thesubstrate was assembled on Fmoc-NH-Rink-MBHA-polystyrene resin eithermanually or on an automated peptide synthesiser by standard methodsinvolving the use of Fmoc-amino acids andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) as coupling agent with at least a 4- or 5-fold excess ofFmoc-amino acid and HBTU. Ser¹ and Pro² were double-coupled. Thefollowing side chain protection strategy was employed; Ser¹(But),Gln⁵(Trityl), Arg^(8,12)(Pmc or Pbf), Ser^(9,10,11)(Trityl),Cys¹³(Trityl). Following assembly, the N-terminal Fmoc-protecting groupwas removed by treating the Fmoc-peptidyl-resin with in DMF. Theamino-peptidyl-resin so obtained was acylated by treatment for 1.5-2 hrat 70° C. with 1.5-2 equivalents of4′,5′-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna & Ullman,(1980) Anal Biochem. 108:156-161) which had been preactivated withdiisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF]. Thedimethoxyfluoresceinyl-peptide was then simultaneously deprotected andcleaved from the resin by treatment with trifluoroacetic acid containing5% each of water and triethylsilane. The dimethoxyfluoresceinyl-peptidewas isolated by evaporation, trituration with diethyl ether andfiltration. The isolated peptide was reacted with4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, theproduct purified by RP-HPLC and finally isolated by freeze-drying fromaqueous acetic acid. The product was characterised by MALDI-TOF MNS andamino acid analysis.

[0144] Natural Substrates

[0145] The activity of the compounds of the invention as inhibitors ofaggrecan degradation may be assayed using methods for example based onthe disclosures of E. C. Arner et al., (1998) Osteoarthritis andCartilage 6:214-228; (1999) Journal of Biological Chemistry, 274 (10),6594-6601 and the antibodies described therein. The potency of compoundsto act as inhibitors against collagenases can be determined as describedby T. Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345.

[0146] Inhibition of Metalloproteinase Activity In Cell/Tissue BasedActivity Test As An Agent To Inhibit Membrane Sheddases Such As TNFConvertase

[0147] The ability of the compounds of this invention to inhibit thecellular processing of TNFα production may be assessed in THP-1 cellsusing an ELISA to detect released TNF essentially as described K. M.Mohler et al., (1994) Nature 370:218-220. In a similar fashion theprocessing or shedding of other membrane molecules such as thosedescribed in N. M. Hooper et al., (1997) Biochem. J. 321:265-279.may betested using appropriate cell lines and with suitable antibodies todetect the shed protein.

[0148] Test As An Agent To Inhibit Cell Based Invasion

[0149] The ability of the compound of this invention to inhibit themigration of cells in an invasion assay may be determined as describedin A. Albini et al., (1987) Cancer Research 47:3239-3245.

[0150] Test An Agent To Inhibit Whole Blood TNF Sheddase Activity

[0151] The ability of the compounds of this invention to inhibit TNFαproduction is assessed in a human whole blood assay where LPS is used tostimulate the release of TNFA. Heparinized (10 Units/ml) human bloodobtained from volunteers. is. diluted 1:5 with medium(RPMI1640+bicarbonate, penicillin, streptomycin and glutamine) andincubated (160 μl) with 20 μl of test compound (triplicates), in DMSO orappropriate vehicle, for 30 min at 37° C. in a humidified (5% CO₂/95%air) incubator, prior to addition of 20 μLPS (E. coli. 0111:B4; finalconcentration 10 μg/ml). Each assay includes controls of diluted bloodincubated with medium alone (6 wells/plate) or a known TNFα inhibitor asstandard. The plates are then incubated for 6 hours at 37° C.(humidified incubator), centrifuged (2000 rpm for 10 min; 4° C. ),plasma harvested (50-100 μl) and stored in 96 well plates at −70° C.before subsequent analysis for TNFα concentration by ELISA.

[0152] Test As An Agent To Inhibit In Vitro Cartilage Degradation

[0153] The ability of the compounds of this invention to inhibit thedegradation of the aggrecan or collagen components of cartilage can beassessed essentially as described by K. M. Bottomley et al., (1997)Biochem J. 323:483-488.

[0154] Pharmacodynamic Test

[0155] To evaluate the clearance properties and bioavailability of thecompounds of this invention an ex vivo pharmacodynamic test is employedwhich utilises the synthetic substrate assays above or alternativelyHPLC or Mass spectrometric analysis. This is a generic test which can beused to estimate the clearance rate of compounds across a range ofspecies. Animals (e,g. rats, marmosets) are dosed iv or po with asoluble formulation of compound (such as 20% w/v DMSO, 60% w/v PEG400)and at subsequent time points (e.g. 5, 15, 30, 60, 120, 240, 480, 720,1220 mins) the blood samples are taken from an appropriate vessel into10U heparin. Plasma fractions are obtained following centrifugation andthe plasma proteins precipitated with acetonitrile (80% w/v finalconcentration). After 30 mins at −20° C. the plasma proteins aresedimented by centrifugation and the supernatant fraction is evaporatedto dryness using a Savant speed vac. The sediment is reconstituted inassay buffer and subsequently analysed for compound content using thesynthetic substrate assay. Briefly, a compound concentration-responsecurve is constructed for the compound undergoing evaluation. Serialdilutions of the reconstituted plasma extracts are assessed for activityand the amount of compound present in the original plasma sample iscalculated using the concentration-response curve taking into accountthe total plasma dilution factor.

[0156] In Vivo Assessment

[0157] Test As An Anti-TNF agent

[0158] The ability of the compounds of this invention as ex vivo TNFαinhibitors is assessed in the rat. Briefly, groups of male WistarAlderley Park (AP) rats (180-210 g) are dosed with compound (6 rats) ordrug vehicle (10 rats) by the appropriate route e.g. peroral (p.o.),intraperitoneal (i.p.), subcutaneous (s.c.). Ninety minutes later ratsare sacrificed using a rising concentration of CO₂ and bled out via theposterior vena cavae into 5 Units of sodium heparin/ml blood. Bloodsamples are immediately placed on ice and centrifuged at 2000 rpm for 10min at 4° C. and the harvested plasmas frozen at −20° C. for subsequentassay of their effect on TNFα production by LPS-stimulated human blood.The rat plasma samples are thawed and 175 μl of each sample are added toa set format pattern in a 96U well plate. Fifty μl of heparinized humanblood is then added to each well, mixed and the plate is incubated for30 min at 37° C. (humidified incubator). LPS (25 μl; final concentration10 μg/ml) is added to the wells and incubation continued for a further5.5 hours. Control wells are incubated with 25 μl of medium alone.Plates are then centrifuged for 10 min at 2000 rpm and 200 μl of thesupernatants are transferred to a 96 well plate and frozen at −20° C.for subsequent analysis of TNF concentration by ELISA.

[0159] Data analysis by dedicated software calculates for eachcompound/dose:${{Percent}\quad {inhibition}\quad {of}\quad {TNF}\quad \alpha} = \frac{{{Mean}\quad {TNF}\quad \alpha \quad ({Controls})} - {{Mean}\quad {TNF}\quad \alpha \quad ({Treated}) \times 100}}{{Mean}\quad {TNF}\quad \alpha \quad ({Controls})}$

[0160] Test As An Anti-arthritic Agent

[0161] Activity of a compound as an anti-arthritic is tested in thecollagen-induced arthritis (CIA) as defmed by D. E. Trentham et al.,(1977) J. Exp. Med. 146,:857. In this model acid soluble native type IIcollagen causes polyarthritis in rats when administered in Freundsincomplete adjuvant. Similar conditions can be used to induce arthritisin mice and primates.

[0162] Test As An Anti-cancer Agent

[0163] Activity of a compound as an anti-cancer agent may be assessedessentially as described in I. J. Fidler (1978) Methods in CancerResearch 15:399-439, using for example the B16 cell line (described inB. Hibner et al., Abstract 283 p75 10th NCI-EORTC Symposium, AmsterdamJun. 16-19, 1998).

[0164] Test As An Anti-emphysema Agent

[0165] Activity of a compound as an anti-emphysema agent may be assessedessentially as described in Hautamaki et al (1997) Science, 277: 2002.

[0166] The invention will now be illustrated but not limited by thefollowing Examples:

[0167] General analytical methods: ¹H-NMR spectra were recorded oneither a Varian ^(Unity)Inova 400MHz or Varian Mercury-VX300MHzinstrument. The central solvent peak of chloroform-d (δ_(H) 7.27 ppm),dimethylsulfoxide-d₆ (δ_(H) 2.50 ppm) or methanol-d₄ (δ_(H) 3.31 ppm)were used as internal references. Low resolution mass spectra wereobtained on a Agilent 1100 LC-MS system equipped with an APCI ionizationchamber.

EXAMPLE 15-(2-{[4′-(4′-fluoro[1,1′-bithenyl]-4-yl)-1-piperazinyl]sulfonyl}ethyl)-2,4-imidazolidinedione

[0168]

[0169] To the solution of 1-(4-fluorophenyl)-phenylpiperazin (0.125 mg,0.48 mmol) in 5 ml of dichloromethane was added triethylamin (0.06 ml,0.5 mmol) and 2-(2,5-dioxo-4-imidazolidinyl)-1-ethanesulfonyl chloride(0.113 ml 0.48 mol). The mixture was stirred for 18 hrs, diluted withDCM to 25 ml, extracted with 1N HCl (5 ml) sat.NaHCO3 (5 ml) and dried,evapdrated, crystallised (EtOH-dioxan). LC-MS (APCI) m/z 446.9 (MH+). 1HNMR δ1.95 m (1H); 2.1 m (1.5H), 3.2 m (13.3H), 4.1 m (1H), 7.05 d (2H),7.25 d (2.1H), 7.65 d (2.2H), 7.80 d (1.8H), 8.0 bs (NH).

[0170] The starting materials were prepared as follows:

[0171] 2-(2,5-dioxo-4-imidazolidinyl)-1-ethanesulfonyl chloride To thesuspension of5-(2-{[2-(2,5-dioxo4-imidazolidinyl)ethyl]disulfanyl}ethyl)-2,4-imidazolidinedione(6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violentlyin three necked flask with gas-inlet tube,thermometer and short refluxcondenser, placed in the ice bath, was bubbled chlorine gas for 15 min(until all precipitate dissolved) at max.temp. +5° C. Then, it wasstirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C.), dissolved in 50 ml of dichloromethane, shaken carefully withsat.NaHCO3 (ca 25 ml),then with 10% sodium thiosulfate, dried,evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968,An. Quim., 64(6):591-606); ¹H NMR: δ2.55 m (1.1H), 2.65 m (1.8H), 2.70 m(1H), 4.55 m (1H).

[0172]5-(2-{[2-(2,5-dioxo-4-imidazolidinyl)ethyl]disulfanyl)ethyl}-2,4-imidazolidinedioneCommercially available RS homocystine (0.18 mol) was suspended in 25 mlwater and of potassium cyanate 1.5 g (0.2 mol) was added and the mixturewas stirred at 100° C. for 45 min. Then it was allowed to cool partiallyand 10 ml of 10% HCl were added at once and the mixture was stirred at100° C. again for 50 min. It was placed in the fridge overnight,crystalswere filtered and washed successively with water and dried in vacuo.LC-MS (APCI) m/z 319.1 (MH+).

[0173] The overall generalised reaction scheme is shown below:

EXAMPLE 2(5R)-5-{[(4-phenyl-1-piperazinyl)sulfonyl]methyl}-2.4-imidazolidinedione

[0174] The title compound was prepared according to the scheme shown inExample 1. To the solution ofR-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride (100 mg, 0.47mmol) in 2.5 ml THF was added the solution of 1-phenylpiperazine (85 mg,0.52 mmol) and 65 ul of triethylamine (0.52 mmol) in 2.5 ml THF viasyringe at once. The mixture was stirred for 3 hrs, precipitatedtriethylammonium chloride was filtered, washed with two small portionsof THF, evaporated and recrystallised from EtOH and a small amount ofAcOH. LC-MS (APCI) m/z 339.1 (MH+). ¹H NMR δ2.5 m (2H), 3.1 bs (6.5H),3.3 m (2.5H), 4.55 m (1H), 6.8 t (1H), 6.9 d (1.88H), 7.2 t (2.05H), 9.1bs (1.7H).

[0175] The starting materials were prepared as follows:

[0176] R-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride To thesuspension ofR-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedione(6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violentlyin three necked flask with gas-inlet tube, thermometer and short refluxcondenser, placed in the ice bath,was bubbled chlorine gas for 15 min(until all precipitate dissolved) at max.temp. +5° C. Then, it wasstirred 15 min more, evaporated to a small volume in vacuo (max.temp 30°C.), dissolved in 50 ml of dichloromethane, shaken carefully withsat.NaHCO3 (ca 25 ml), then with 10% sodium thiosulfate, dried,evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968,An. Quim., 64(6:591-606); ¹H NMR (DMSO-d₆): δ3.21 m (1.1H), 3.3 m(0.7H).4, 65 m (1H).

[0177]R-5-({[(2,5-dioxo4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedioneCommercially available R cystine (0.18 mol) was suspended in 25 ml waterand of potassium cyanate 1.5 g (0.2 mol) was added and the mixture wasstirred at 100° C. for 45 min. Then it was allowed to cool partially and10 ml of 10% HCl were added at once and the mixture was stirred at 100°C. again for 50 min. It was placed in the fridge overnight, crystalswere filtered and washed successively with water and dried in vacuo.LC-MS (APCI) m/z 291 (MH+).

EXAMPLE 3(5S)-5-{[(4-phenyl-1-piperazinyl)sulfonyl]methyl}-2,4-imidazolidinedione

[0178] The title compound was prepared according to the scheme shown inExample 1. To the solution ofS-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride (100 mg,0.47mmol) in 2.5 ml THF was added the solution of 1-phenylpiperazine (85 mg,0.52 mmol) and 65 ul of triethylamine (0.52 mmol) in 2.5 ml THF viasyringe at once. The mixture was stirred for 3 hrs, precipitatedtriethylamhonium chloride was filtered, washed with two small portionsof THF, evaporated and recrystallised from EtOH and a small amount ofAcOH. LC-MS (APCI) m/z 339.1 (MH+). ¹H NMR: 8 2.5 m (2H),3.1 bs (6.5H),3.3 m (2.5H), 4.55 m (1H), 6.8 t (1H), 6.9 d (1.88H), 7.2 t (2.05H), 9.1bs (1.7H)

[0179] The starting materials were prepared as follows:

[0180] S-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride To thesuspension ofS-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedione(6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violentlyin three necked flask with gas-inlet tube,thermometer and short refluxcondenser,placed in the ice bath,was bubbled chlorine gas for 15 min(until all precipitate dissolved) at max.temp. +5° C. Then,it wasstirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C.), dissolved in 50 ml of dichloromethane,shaken carefully withsat.NaHCO3 (ca 25 ml), then with 10% sodium thiosulfate, dried,evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968,An. Quim., 64(6):591-606); ¹H NMR (DMSO-d₆): δ3.2 m (0.9H, 3.35 m(0.9H), 4.50 m (1H).

[0181]S-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedioneConmmercially available S cystine (0.18 mol) was suspended in 25 mlwater and of potassium cyanate 1.5 g (0.2 mol) was added and the mixturewas stirred at 100° C. for 45 min. Then it was allowed to cool partiallyand 10 ml of 10% HCl were added at once and the mixture was stirred at100° C. again for 50 min. It was placed in the fridge overnight,crystalswere filtered and washed successively with water and dried in vacuo.LC-MS (APCI) m/z 291.1 (MH+).

EXAMPLE 4 (R)-5-(([4-(4′-fluoro[1,1′-biphenyl]-4-ylI)-1-piperazinyl]sulfonyl)methyl)-2,4-imidazolidinedione

[0182]

[0183] [(R)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride (0.0127 g,0.060 mmol), 1-(4′-fluoro [1,1′-biphenyl]-4-yl)piperazine (0.0154 g,0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and drytetrahydrofuran (0.70 mL) were stirred at room temperature over night.Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and themixture was shaken over night. The white suspension was carefullytransferred to a round-bottomed flask, the resin was rinsed withtetrahydrofuran (2×1 mL) and washings were transferred to the bulk ofsuspension. The solvent was evaporated, the white solid was suspended inwater (5 mL), collected on a filter, washed with water (2×1 mL), suckedfree of water and dried in vacuo at 45° C. over night to afford approx.0.010 g of the title compound. LC-MS (APCI) m/z 434 (MH+). ¹H NMR(DMSO-d₆) δ10.8 (1H, bs), 7.98 (1H, d, J=2 Hz), 7.63 (2H, dd, J₁=5 Hz,J₂=9 Hz), 7.53 (2H, d, J=9 Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, J=9Hz), 4.45 (1H, ddd, J₁=2 Hz, J₂=4 Hz, J₃=6 Hz), 3.51 (1H, dd, J₁=5 Hz,J₂=7 Hz), 3.44 (1H, dd, J₁=5 Hz, J₂=4 Hz), 3.35-3.25 (8H, m's; obscuredby water signal) ppm. ¹³C NMR (DMSO-d₆) δ173.7, 161.3 (d, J=243 Hz),157.3, 149.8, 136.4 (d, J=3 Hz), 130.1, 127.7 (d, J=8Hz), 127.2, 116.2,115.5 (d, J=21 Hz), 53.4, 49.4, 48.0, 44.9.

[0184] The starting materials were prepared as follows:

[0185] [(R)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride wasprepared according to Mosher et al, 1958, J. Org. Chem 23:1257.

[0186] 1-(4′-Fluoro [1,1′-biphenyl]4-yl)piperazine4-Bromo-4′-fluorobiphenyl (4.46 g, 17.8 mmol), N-tert-butoxycarbonylpiperazine (3.97 g, 21.3 mmol), sodium tert-butoxide (2.39 g, 24.9mmol),racemic 2,2′-bis(diphenylphosphino)- 1,1′-binaphthyl (rac-BINAP) (0.082g, 0.131 mmol), bis-(dibenzylideneacetone)palladium (0) (0.041 g, 0.045mmol) and dry toluene (45 mL) were stirred at 80° C. under nitrogenatmosphere for six hours. The warm mixture was filtered, the solids werewashed twice with warm toluene and the filtrate was concentrated invacuo giving an orange-red crude, which was stirred with ether (50 mL)for two hours. The solid was filtered off, washed with small volumes ofether and dried in vacuo at 45° C. over night to give 5.57 g (88% yield)of tert-butyl 4-(4′-fluoro [1,1′-biphenyl]4-yl)-1-piperazinecarboxylate.This product (5.52 g, 15.5 mmol) was dissolved in dioxane (150 mL) andstirred with 4M hydrochloric acid (8.1 mL) at RT over night.Concentrated hydrochloric acid (3.0 mL) was added and stirring wascontinued at 45° C. for 1.5 hours and at 60° C. for 1 hour. The solutionwas concentrated to dryness and the solid was triturated with ether (100mL), filtered, washed with small volumes of ether and dried in vacuo at45° C. for two hours to give 5.26 g (103% yield) of 1-(4′-fluoro[1,1′-biphenyl]-4-yl)piperazine dihydrochloride as a light-yellow salt.

[0187] LC-MS (APCI) m/z 257 (MH+). ¹H NMR (DMSO-d₆) δ9.40 (2H, bs), 7.64(2H, dd, J₁=6 Hz, J₂=9 Hz), 7.55 (2H, d, J=9 Hz), 7.24 (2H, t, J=9 Hz),7.07 (2H, d, J=9 Hz), 3.46-3.41 (4H, m), 3.25-3.17 (4H, m).

[0188] The salt was treated with aqueous sodium hydroxide solution andthe base was taken up in dichloro-methane. Drying with Na₂SO₄, filteringand concentrating the organic phase gave the title compound as anoffwhite solid.

[0189]¹H NMR (DMSO-d₆) δ7.61 (2H, dd, J₁=6 Hz, J₂=9 Hz), 7.49 (2H, d,J=9 Hz), 7.22 (2H, t, J=9 Hz), 6.98 (2H, d, J=9 Hz), 3.10-3.06 (4H, m),2.86-2.81 (4H, m).

EXAMPLE 5

[0190] Using an analogous procedure to that described in Example 4,[(4R)-2,5-dioxoimidazolidinyl]methanesulfonyl chloride was reacted withthe appropriate primary or secondary amine to give the compounds listedbelow. All the amines employed are commercially available.

[0191] The Table below gives the Amine group for each compound of theabove structure.

MW. 353.40 MW. 355.39 m/z 354 (MH+) m/z 356 (MH+)

MW. 357.36 MW. 421.52 m/z 358 (MH+) m/z 422 (MH+)

MW. 422.29 MW. 433.49 m/z 423 (MH+) m/z 434 (MH+)

MW. 437.91 m/z 438 (MH+)

EXAMPLE 6 (S)-5-(([4-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-piperazinyl]sulfonyl)methyl)-2,4-imidazolidinedione

[0192]

[0193] [(S)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride (0.0127 g,0.060 mmol), 1-(4′-fluoro [1,1′-biphenyl]-4-yl)piperazine (0.0154 g,0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and drytetrahydrofuran (0.70 mL) were stirred at room temperature over night.Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and themixture was shaken over night. The white suspension was carefullytransferred to a round-bottomed flask, the resin was rinsed withtetrahydrofuran (2×1 mL) and washings were transferred to the bulk ofsuspension. The solvent was evaporated, the white solid was suspended inwater (5 mL), collected on a filter, washed with water (2×1 mL), suckedfree of water and dried in vacuo at 45° C. over night to afford approx.0.010 g of the title compound. LC-MS (APCI) m/z 433 (MH+). ¹H NMR(DMSO-d₆) δ10.8 (1H, br s), 7.98 (1H, d, J=2 Hz), 7.63 (2H, dd, J₁=5 Hz,J₂=9 Hz), 7.53 (2H, d, J=9 Hz), 7.23 (2H, t, J=9 Hz), 7.05 (2H, d, J=9Hz), 4.45 (1H, ddd, J₁=2 Hz, J₂=4 Hz, J₃=6 Hz), 3.51 (1H, dd, J₁=15 Hz,J₂=7 Hz), 3.44 (1H, dd, J₁=15 Hz, J₂=4 Hz), 3.35-3.25 (8H, m's; obscuredby water signal). ¹³CNMR(DMSO-d₆) δ173.7, 161.3 (d, J=243 Hz), 157.3,149.8, 136.4 (d, J=3 Hz), 130.1, 127.7 (d, J=8Hz), 127.2, 116.2, 115.5(d, J=21 Hz), 53.4, 49.4, 48.0, 44.9.

[0194] The starting materials were prepared as follows:

[0195] [(S)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride wasprepared according to Mosher et al, 1958, J. Org. Chem 23:1257.

[0196] 1-(4′-Fluoro [1,1′-biphenyl]-4-yl)piperazine was preparedaccording to Example 4.

EXAMPLE 7

[0197] Using an analogous procedure to that described in Example 6,[(4S)-2,5-dioxoimidazolidinyl]methanesulfonyl chloride was reacted withthe appropriate primary or secondary amine to give the compounds listedbelow. All the amines employed are commercially available.

[0198] The Table below gives the Amine group for each compound of theabove structure.

MW. 353.40 MW. 355.39 m/z 354 (MH+) m/z 356 (MH+)

MW. 357.36 MW. 421.52 m/z 358 (MH+) m/z 422 (MH+)

MW. 422.29 MW. 433.49 m/z 423 (MH+) m/z 434 (MH+)

MW. 437.91 m/z 438 (MH+)

EXAMPLE 8

[0199] Hydantoins with the following general structure were synthesised(where E is carbon or a heteroatom):

[0200] Representative synthetic route:(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonvlmethyl]-5-methyl-imidazolidine-2,4-dione.

[0201] Reagents: a) MeSO₂Cl, DCM, 0° C., 2.5 h. b) i. LHMDS, THF, 45min. ii. MeOAc, THF, 40 min. c) KCN, (NH₄)₂CO₃, 50% EtOH/H₂O, 70° C., 17h. SULFONYL-AMIDE INTERMEDIATES Structure Analysis⁽¹⁾

m/z 258 (MH+)

m/z 291 (MH+)

m/z 310 (MH+)

m/z 267 (MH+)

m/z 259 (MH+)

m/z 273 (MH+)

m/z 243 (MH+)

m/z 274 (MH+)

[0202] 4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine4-(4-Fluoro-phenyl)piperidine hydrochloride (2.16 g; 10 mmol) anddiisopropylethylamine (4.35 ml; 25 mmol) was dissolved in DCM (60 ml)and cooled under nitrogen on a ice/water bath. Methanesulfonyl chloride(1.56 ml; 10.1 mmol) was dissolved in DCM (5 ml) and added droppwiseduring 2 min. The reaction mixture was stirred for 2.5 h on theice/water bath. The reaction mixture was washed with dilute HCl (aq),pH=2, H₂O, and 1M Na₂CO₃. The organic phase was dried (Na2SO₄), filteredand evaporated to give a crude product that was recrystallised fromTHF/n-Heptane. The colourless crystalls was removed by filtration anddried under vaccum at 45° C. Obtained 1.96 g (76% yield) of the titlecompound. LC-MS (APCI) m/z 258 (MH+). ¹H NMR(DMSO-d₆): δ7.31 (m, 2H),7.12 (m, 2H), 3.67 (m, 2H), 2.80 (dt, 2H), 2.64 (m, 1H), 1.85 (m, 2H),1.65 (m, 2H).

[0203] 5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine Thetitle compound was prepared as described in the synthesis of4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine.5-Chloro-2-(piperidine4-yloxy)-pyridine (2.13 g; 10 mmol) (preparationof this compound was made as described in WO 99-GB2801),diisopropylethylamine (2.20ml; 12.5mmol) and Methanesulfonyl chloride(1.56 ml; 10.1 mmol) gave 2.14 g (74%) of the title compound. LC-MS(APCI) m/z 291 (MH+). ¹H NMR (DMSO-d₆): δ8.20 (d, 1H), 7.81 (dd, 1H),6.87 (d, 1H), 5.09 (m, 1H), 3.41-3.30 (m, 2H), 3.15-3.06 (m, 2H), 2.90(s, 3H), 2.04 (m, 2H), 1.75 (m, 2H).

[0204] 1-(methylsulfonyl)4-[5-(trifluoromethyl)pyridin-2-yl]piperazine1-[5-(Trifluoromethyl)-Pyridin-2-yl]-piperazine (1.0 g; 4.3 mmol) andDiisopropylethylamine (0.9 ml; 5.4 mmol) was dissolved in DCM (10 ml).Molecular sieves (4A) was added and the solution was cooled on aice/water bath. Methanesulfonylchloride (0.9 ml; 12 mmol) was added anda slurry formed that was stirred for 15 min, the reaction mixture wasallowed to reach room temperature and after 1 h. the reaction wasquenched by adding 5% KHCO₃. Evaporation of solvents and the residue wasdissolved between DCM and 5% KHCO₃. Separation and extraction of thewaterphase with DCM (1×). The combined organic phases was dried (MgSO₄),filtered and evaporated to give a crude product as a slightly yellowsolid. Recrystallised (3×) from EtOAc/Heptan gave the title compound ascolourless crystalls. Obtained 1.06 g (79% yield) of the title compound.Purity >95% (H4PLC, 254 nm) LC-MS (APCI) m/z 310 (MH+). ¹H-NMR(DMSO-d₆):δ8.44 (1H, bs), 7.85 (1H, dd), 7.02 (1H, d), 3.77 (4H, bt), 3.20 (4H,bt), 2.90 (3H, s).

[0205] The following compounds were prepared as described in thesynthesis of1-(methylsulfonyl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine

[0206] 6-[4-(methylsulfonyl)piperazine-1-yl]pyridine-3-carbonitrile6-(1-Piperazino)-pyridine-3-carbonitrile (2.07 g; 11 mmol),Diisopropylethylamine (2.4 ml; 13.8 mmol) and Methanesulfonylchloride(0.86 ml; 1 mmol) in DCM (20 ml) gave 2.53 g (86%) of the titlecompound. Purity >95% (NMR). LC-MS (APCI) m/z 267 (MH+).¹H-NMR(DMSO-d₆): δ8.52 (1H, dd), 7.90 (1H, dd), 7.00 (1H, d), 3.79 (4H,brt), 3.19 (4H, bt), 2.90 (3H, s).

[0207] 1-(4-fluorophenyl)4-(methylsulfonyl)piperazine1-(4-Fluorophenyl)-piperazine (1.98 g; 11 mmol), Diisopropylethylamine(2.4 ml; 13.8 mmol) and Methanesulfonylchloride (0.86 ml; 11 mmol) inDCM (20 ml) gave 2.46 g (86%) of the title compound. Purity >95% (NMR).LC-MS (APCI) m-l/z 259 (MH+). ¹H-NMR(DMSO-d₆): δ7.11-6.96 (4H, m),3.28-3.20 (4H, m), 3.20-3.14 (4H, m), 2.92 (3H, s).

[0208] 1-[(4-fluorophenyl)methyl]-4-(methylsulfonyl)piperazine1-(4-Fluor-benzyl)-piperazine (2.14 g; 11 mmol), Diisopropylethylamine(2.4 ml; 13.8 mmol) and Methanesulfonylchloride (0.86 ml; 1 mmol) in DCM(20 ml) gave 1.97 g (65%) of the title compound. Purity >95% (NMR) LC-MS(APCI) m/z 273 (MH+). ¹H-NMR(DMSO-d₆): δ7.40-7.28 (2H, m), 7.21-7.10(2H, m), 3.50 (2H, bs), 3.10 (4H, m), 2.87 (3H, bs), 2.44 (4H, m).

[0209] 2-[4-(methylsulfonyl)piperazin-1-yl)pyrimidine1-(2-Pyrimidyl)-piperazine dihydrochloride (2.61 g; 11 mmol) andDiisopropylethylamine (7.2 ml; 41.3 mmol) was stirred in DCM (20 ml) for30 min. The precipitated salts was removed by filtration and solventsevaporated, residue was redissolved in DCM (20 ml).Diisopropylethylamine (2.4 ml; 1 mmol) and 4A mol. sieves was added, theyellow solution was cooled on ice/water bath and Methanesulfonylchloride(0.86 ml; 11 mmol) was added. The resulting red solution was stirred for15 min, the reaction mixture was allowed to reach room temperature andafter 1 h. the reaction was quenched by adding 5% KHCO₃. Evaporation ofsolvents and the residue was dissolved between DCM and 5% KHCO₃.Separation difficult due to foam formation. Waterphase was saturatedwith NaCl and pH adjusted to 10-11. Extraction with EtOAc (3×). Thecombined organic phases was dried (K₂CO₃), filtered and evaporated togive a crude product as a red solid. Recrystallised (3×) fromEtOAc/Heptan gave the title compound as a red powder. Obtained 0.6 g(22%) of the title compound. Purity >95% (NMR). LC-MS (APCI) m/z 243(MH+). ¹H-NMR(DMSO-d₆): δ8.39 (2H, d), 6.68 (1H, t), 3.85 (4H, bt), 3.17(4H, bt), 2.88 (3H, s).

[0210] 4-(4-chlorophenyl)-1-(methylsulfonyl)piperidine The titlecompound was prepared as described in the synthesis of4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine.4-(4-Chlorophenyl)piperidine hydrochloride (0.9 g, 3.9 mmol),diisopropylethylamine (1.7 ml, 9.7 mmol) and methanesulfonylchloride(0.33 ml, 4.3 mmol) in DCM (30 ml) and gave 0.82g (78%) of the titlecompound after recrystallisation from EtOAc/ Heptane. Purity >95%.LC-MS(APCI) m/z 274 (MH+). ¹H NMR CDCl₃: δ1.83 (2H, dd); 1.92-2.01 (2H,m); 2.55-2.68 (1H, m); 2.79 (2H, dt); 2.85 (3H, s); 3.97 (2H, d); 7.16(2H, d); 7.32 (2H, d). ESTER INTERMEDIATES Structure Analysis

m/z 195 (MH+) ¹H-NMR

m/z 181 (MH+)

m/z 158 (MH+ -boc)

[0211] All other esters used are commercially available or earlierdescribed.

[0212] 4-Pyrimidin-2-yl-butyric acid ethyl ester 2-Bromopyrimidine (1.0g, 6.3 mmol) was slurried in dry THF (8mL). N₂ (g) was bubbled throughthe slurry for 5 min. Pd(CH₃CN)₂Cl₂ (8 mg, 0.03 mmol) and PPh₃ (23.6 mg,0.09 mmol) was added. Under N₂-atmosphere 4-Ethoxy4-oxo-butylzincbromide(0.5M/THF) (15 mL, 7.5 mL) was added in one portion. The resulting brownsolution was stirred at room temperature for 2 h. H₂O (5mL) was addedand the mixture stirred for 60 min. before evaporation of solvents. Theresidue was redissolved in DCM (150 mL) and washed with 0.5 Mtrisodiumcitrate (100 mL), H₂O (100 mL) and brine (lOOmL), dried(MgSO₄), filtered and evaporated to give 1.3 g of an orange oil. Thecrude product was purified on 70 g of Si-60 gel using a gradient of 100%Heptane to 100% EtOAc as eluent. The fractions containing the productwas collected and solvent evaporated to give a yellow oil. Purity byNMR>95% was considered enough for our need. Obtained 1.12 g (92% yield)of the title compound. LC-MS (APCI) m/z 195 (MH+). ¹H-NMR(CDCl₃): δ8.67(d, 2H), 7.14 (t, 1H), 4.12 (q, 2H), 3.02 (t, 2H), 2.41 (t, 2H), 2.18(q, 2H), 1.25 (t, 3H).

[0213] 3-Pyrimidin-2-yl-propionic acid ethyl ester 2-Bromopyrimidine(1.0 g, 6.3 mmol) was dissolved in THF (8 mL) and bubbled through withnitrogen. Pd(MeCN)₂Cl₂ (8 mg, 0.03 mmol) and PPh₃ (23.6 mg, 0.09 mmol)was added followed by addition of 3-ethoxy-3-oxopropylzinkbromid (15 mL,7.5 mmol). The reaction was stirred at rt for several days. The crudeproduct was purified on silica with Heptane-EtOAc 3:1 as eluent giving0.60 g (52%) of the title compound. LC-MS (APCI) m/z 181 (MH+).

[0214] tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylatetert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (3.6 g,14 mmol) and 10% Pd/C moistered with water (0.8 g) was mixed in MeOH (75mL) and stirred under H₂ (1 atm) for 4 h. The mixture was filteredthrough Celite and concentrated to give the title compound (3.6 g, 99%).LC-MS (APCI) m/z 158 (MH+-boc). ¹H NMR (CDCl₃): δ4.07 (2 H, bs); 3.68 (3H, s); 2.72 (2 H, t); 2.25 (2 H, d, J=7.1 Hz); 2.01-1.86 (1 H, m); 1.68(2 H, d); 1.46 (9 H, s); 1.23-1.08 (2 H, m). KETONE INTERMEDIATES

R E R2 Analysis

CH Me m/z 300 (MH+)

CH

H-NMR. see exp. part.

CH

m/z 394 (MH+)

CH

m/z 406 (MH+)⁽¹⁾

CH Me m/z 333 (MH+)⁽¹⁾

CH

m/z 423 (MH+)⁽¹⁾

CH

m/z 427 (MH+)⁽¹⁾

CH

m/z 439 (MH+)⁽¹⁾

CH

m/z 347 (MH+)⁽¹⁾

CH

m/z 361 (MH+)⁽¹⁾

CH

m/z 375 (MH+)⁽¹⁾

CH

m/z 425 (MH+)⁽¹⁾

CH

m/z 423 (MH+)⁽¹⁾

CH

m/z 417 (MH+)⁽¹⁾

CH

m/z 446 (MH+)⁽¹⁾

CH

m/z 372 (MH+)⁽¹⁾

CH

m/z 476 (MH+)⁽¹⁾

CH

m/z 432 (MH+)⁽¹⁾

CH

m/z 395 (MH+)⁽¹⁾

CH

m/z 413 (MH+)⁽¹⁾

CH

m/z 385 (MH+)⁽¹⁾

CH

—

CH

m/z 414 (MH+)⁽¹⁾

CH

m/z 392 (MH+)⁽¹⁾

CH

m/z 384 (MH+)⁽¹⁾

CH

m/z 405 (MH+)⁽¹⁾

CH

m/z 352 (MH+)⁽¹⁾

CH

m/z 400 (MH+)⁽¹⁾

CH

m/z 429 (MH+)⁽¹⁾

N Me m/z 352 (MH+)⁽¹⁾

N Me m/z 309 (MH+)⁽¹⁾

N Me m/z 301 (MH+)⁽¹⁾

N Me m/z 315 (MH+)⁽¹⁾

N Me m/z 285 (MH+)⁽¹⁾

CH

m/z 517 (MH+)⁽¹⁾

[0215] 1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-propan-2-one.4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (100 mg; 0.39 mmol) wasdissolved in dry THF (3 mL) under a protective nitrogen atmosphere.Lithium bis(trimethylsilyl)amide as a 1.0 M solution in THF (1.0 mL; 1.0mmol) was added in one portion at room temperature, the resulting yellowsolution was stirred for 45 min. Methylacetate (50 mg; 0.68 mmol)dissolved in dry THF (0.5 mL) was added, the mixture was stirred at roomtemperature for 40 min. The reaction was quenched by adding NH₄Cl (sat.)(2 mL). The mixture was evaporated and the resulting solid was dissolvedin a mixture of DCM and H₂O. The organic phase was separated and washedwith brine, dried (MgSO₄), filtrated and evaporated. The crude productwas purified on 20 g of Si-60 gel using a gradient of 100% Heptane to50% EtOAc, a flow of 20 mL/min was used and UV=254 nm was used fordetection, The fractions containing the product was evaporated and thisgave the title compound as a colourless solid. Obtained 70 mg (59%yield). TLC(Si-60; EtOAc:Heptane (2:1)): R_(f)=0.65 LC-MS (APCI) m/z300.1 (MH+). ¹H-NMR(CDCl₃): δ7.17 (m, 2H), 7.01 (m, 2H), 4.02 (s, 2H),3.93 (m, 2H), 2.94 (dt, 2H), 2.63 (m, 1H), 2.46 (s, 3H) 1.91 (m, 2H),1.77 (m, 2H).

[0216] The following compounds were prepared as described in thesynthesis of 1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-propan-2-one.

[0217] 1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-4-phenyl-butan-2-one4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (100 mg; 0.39 mmol),Methyl-3-phenylpropionate (112 mg; 0.68 mmol) and Lithiumbis(trimethylsilyl)amide 1.0 M/THF (1.0 mL; 1.0 mmol) gave 93 mg (61%)of the title compound. TLC(Si-60; EtOAc:Heptane (2:1)): R_(f)=0.68¹H-NMR(CDCl₃): δ7.30-7.10 (m, 7H), 6.99 (m, 2H), 3.97 (s, 2H), 3.79 (m,2H), 3.11 (t, 2H), 2.94 (t, 2H), 2.83 (dt, 2H) 2.57 (m, 1H), 1.83 (m,2H), 1.70 (m, 2H).

[0218]1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-5-imidazol-pentan-2-one4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (100 mg; 0.39 mmol),4-imidazol-1yl-butyric acid ethyl ester (127 mg; 0.70 mmol) and Lithiumbis(trimethylsilyl)amide 1.0 M/THF (1.0 mL; 1.0 mmol) gave 75 mg (48%)of the title compound. LC-MS (APCI) m/z 394 (MH+). ¹H-NMR(CDCl₃): δ7.48(s, 1H), 7.16 (m, 2H), 7.08 (s, 1H), 7.02 (m, 2H), 6.93 (s, 2H), 4.00(t, 2H), 3.97 (s, 2H), 3.90 (m, 2H), 2.92 (dt, 2H), 2.77 (t, 2H), 2.63(m, 1H), 2.12 (q, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0219]1-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-one4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (150 mg; 0.39 mmol) wasdissolved in dry THF (3 mL) and cooled on an ice/brine mixture. Lithiumbis(trimethylsilyl)amide as a 1.0 M solution in THF (1.5 mL; 1.5 mmol)was added and the mixture was stirred for 40 min.4-Pyrimidin-2-yl-butyric acid ethyl ester (169 mg; 0.87 mmol) in THF(0.5 mL) was added, the reaction was stirred for 30 min and then allowedto reach room temperature.

[0220] After 2 h. LC/MS analysis of the reaction mixture showed >98%conversion of the starting material and the reaction was quenched byadding saturated NH₄Cl (aq) (2 mL). The mixture was evaporated and theresulting solid was dissolved in a mixture of DCM and 5% KHCO₃. Theorganic phase was separated and the water phase was extracted once withDCM. The combined organic phases was washed with brine, dried (MgSO₄),filtered, and evaporated to give a yellow oil. The oil was dissolved inEtOAc and isoHexane was added until a solid formed. Evaporation ofsolvent gave a yellow solid crude product. This material was analysedusing LC/MS only and used without fuirther purification in the nextstep. Obtained 234 mg of the crude title compound. LC-MS (APCI) m/z406.1 (MH+).

[0221] The following compounds were prepared as described in thesynthesis of1-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-one.They were obtained as crude products and used without furtherpurification.

[0222]1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-propan-2-oneStarting from 5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine(150 mg; 0.51 mmol), Methylacetate (61 mg; 0.82 mmol) and Lithiumbis(trimethylsilyl)amide 1.0M/THF (1.3 ml; 1.3 mmol). Obtained 161 mg ofthe crude title compound. Used without further purification. LC-MS(APCI) m/z 333.1 (MH+).

[0223]1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]4-phenyl-butan-2-oneStarting from 5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine(150 mg; 0.51 mmol), Methyl-3-phenylpropionate (126 mg; 0.77 mmol) andLithium bis(trimethylsilyl)amide 1.0 M/THF (1.3 ml; 1.3 mmol). Obtained258 mg of the crude title compound. Used without further purification.LC-MS (APCI) m/z 423.2 (MH+).

[0224]1-[4-5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-imidazol-1-yl-pentan-2-oneStarting from 5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine(150 mg; 0.51 mmol), 4-imidazol-1yl-butyric acid ethyl ester (140 mg;0.77 mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3 ml; 1.3mmol). Obtained 268 mg of the crude title compound. Used without furtherpurification. LC-MS (APCI) m/z 427.2 (MH+).

[0225]1-[4(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-oneStarting from 5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine(150 mg; 0.51 mmol), 4-Pyrimidin-2-yl-butyric acid ethyl ester (147 mg;0.76 mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3 ml; 1.3mmol). Obtained 244 mg of the crude title compound. Used without furtherpurification. LC-MS (APCI) m/z 439.2 (MH+).

[0226]1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-butan-2-one LC-MS(APCI) m/z 347 (MH+)

[0227]1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-pentan-2-oneLC-MS (APCI) m/z 361 (MH+)

[0228]1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]4-methyl-pentan-2-oneLC-MS (APCI) m/z 375 (MH+)

[0229]1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]4-pyrimidin-2-yl-butan-2-oneLC-MS (APCI) m/z 425 (MH+)

[0230]1-({4-[(5-Chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-3-(3-methylphenyl)propan-2-oneLC-MS (APCI) m/z 423 (MH+)

[0231]1-({4-[(5-Chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-3-tetrahydro-2H-pyran4-ylpropan-2-oneLC-MS (APCI) m/z 417 (MH+)

[0232]1-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-5-morphofin-4-ylpentan-2-oneLC-MS (APCI) m/z 446 (MH+)

[0233]5-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)4-oxopentanenitrileLC-MS (APCI) m/z 372 (MH+)

[0234] 1,1-dimethylethyl5-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-oxopentylcarbamateLC-MS (APCI) m/z 476 (MH+)

[0235]1-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-morpholinfylbutan-2-oneLC-MS (APCI) m/z 432 (MH+)

[0236]2-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1-phenylethanoneLC-MS (APCI) m/z 395 (MH+)

[0237]2-({4-[(S-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1-(4-fluorophenyl)ethanoneLC-MS (APCI) m/z 413 (MH+)

[0238]2-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1-(1H-imidazol4-yl)ethanoneLC-MS (APCI) m/z 385 (MH+)

[0239]4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)acetyl]benzamiaen.d.

[0240]1-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-(1H-1,2,4-triazol-1-yl)butan-2-oneLC-MS (APCI) m/z 414 (MH+)

[0241]1-{[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}-4pyrimidin-2-ylbutan-2-oneLC-MS (APCI) m/z 392 (MH+)

[0242] 1-{[b4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}-3tetrahydro-2H-pyran-4-ylpropan-2-oneLC-MS (APCI) m/z 384 (MH+)

[0243] 4-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}acetyl)benzamideLC-MS (APCI) m/z 405 (MH+)

[0244]2-{[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}-1-(1H-imidazol4-yl)ethanoneLC-MS (APCI) m/z 352 (MH+)

[0245]1-{[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}-3-tetrahydro-2H-pyran4-ylpropan-2-oneLC-MS (APCI) m/z 400 (MH+)

[0246]1-{[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}-5-morpholin-4-ypentan-2-oneLC-MS (APCI) m/z 429 (MH+)

[0247]1-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-yl}sulfonyl)propan-2-oneLC-MS (APCI) m/z 352.1 (MH+)

[0248]6-{4-[(2-oxopropyl)sulfonyl]piperazin-1-yl}pyridine-3-carbonitrile LC-MS(APCI) m/z 309.1 (MH+)

[0249] 1-{[4-(4-fluorophenyl)piperazine-1-yl]sulfonyl}propan-2-one LC-MS(APCI) m/z 301.1 (MH+)

[0250]1-({4-[(4-fluorophenyl)methyl]piperazine-1-yl}sulfonyl)propan-2-oneLC-MS (APCI) m/z 315.1 (MH+)

[0251] 1-[(4-pyrimidin-2-ylpiperazine-1-yl)sulfonyl]propan-2-one LC-MS(APCI) m/z 285.1 (MH+)

[0252] 1,1-dimethylethyl4-[3-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-2-oxopropyl]piperidine-1-carboxylateLC-MS (APCI) m/z 517 (MH+). HYDANTOINS OF FORMULA I

R E R2 Analysis

CH Me m/z 370 (MH+)⁽¹⁾

CH

m/z 460 (MH+)⁽¹⁾

CH

m/z 464 (MH+)⁽¹⁾

CH

m/z 476 (MH+)⁽¹⁾

CH Me m/z 403 (MH+)⁽¹⁾

CH

m/z 493 (MH+)⁽¹⁾

CH

m/z 497 (MH+)⁽¹⁾

CH

m/z 509 (MH+)⁽¹⁾

CH

m/z 417 (MH+)⁽¹⁾

CH

m/z 431 (MH+)⁽¹⁾

CH

m/z 445 (MH+)⁽¹⁾

CH

m/z 495 (MH+)⁽¹⁾

CH

m/z 493 (MH+)⁽¹⁾

CH

m/z 487 (MH+)⁽¹⁾

CH

m/z 517 (MH+)⁽¹⁾

CH

m/z 442 (MH+)⁽¹⁾

CH

m/z 547, 490 (MH+), -tBu⁽¹⁾

CH

m/z 502 (MH+)⁽²⁾

CH

m/z 465 (MH+)⁽²⁾

CH

m/z 483 (MH+)⁽²⁾

CH

m/z 455 (MH+)⁽²⁾

CH

m/z 508 (MH+)⁽²⁾

CH

m/z 484 (MH+)⁽²⁾

CH

m/z 462 (MH+)⁽¹⁾

CH

m/z 454 (MH+)⁽¹⁾

CH

m/z 475 (MH+)⁽¹⁾

CH

m/z 422 (MH+)⁽²⁾

CH

m/z 470 (MH+)⁽¹⁾

CH

m/z 499 (MH+)⁽¹⁾

N Me m/z 422 (MH+)⁽¹⁾

N Me m/z 379 (MH+)⁽¹⁾

N Me m/z 371 (MH+)⁽¹⁾

N Me m/z 385 (MH+)⁽¹⁾

N Me m/z 355 (MH+)⁽¹⁾

CH

m/z 446 (MH+)⁽¹⁾

CH

m/z 472 (MH+)⁽¹⁾

CH

m/z 4o3 (MH+)⁽¹⁾

CH

m/z 466 (MH+)⁽¹⁾

CH

m/z 530 (MH+ -boc)⁽¹⁾

CH

m/z 486 (MH+ -boc)⁽¹⁾

CH

m/z 524 (MH+)⁽¹⁾

[0253](5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneThe ketone 1-[4-4(Fluorophenyl)-piperidine-1-sulfonyl]-propan-2-one (68mg; 0.23 mmol), KCN (30 mg; 0.46 mmol) and (NH₄)₂CO₃ (111 mg; 1.1 6mmol) was suspended in 50% EtOH/H₂O (8 mL) in a 22 mL sealed tube andheated to 70° C., a solution was formed. The mixture was stirred at 70°C. for 17 h. a solid formed in the tube, the mixture was cooled to roomtemperature and solvent evaporated, the residue was suspended in waterand pH adjusted to pH=6 using 1.0M HCl and preciptated product removedby filtration and washed with water. The water phase was saturated withNaCl and extracted with MeCN. The solid material and MeCN solutions wascombined and evaporated. The crude product was purified using asemipreparative HPLC system and a C-18 column with MeCN/H₂O+0.1% TFA aseluent. Fractions containing the product was combined and solventremoved by evaporation to give the title compound as a colourless solid.Obtained 53 mg (62% yield). Purity by NMR >98% LC-MS (APCI) m/z 370.0(MH+). ¹H-NMR (DMSO-d₆): δ10.74 (s, 1H), 8.02 (s, 1H), 7.31 (m, 2H),7.12 (m, 2H), 3.61 (m, 2H), 3.51 (d, 1H), 3.34 (d, 1H), 2.86 (m, 2H),2.63 (m, 1H), 1.82 (m, 2H), 1.63 (m, 2H), 1.34 (s, 3H).

[0254] 5(5R,S)-5-[4-(4-Fluoro-thenyl)-piperidine-1-sulfonylmethyl]-5-phenethyl-imidazolidine-2,4-dioneThe title compound was prepared as described in the synthesis of(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione.1-[4-4(Fluorophenyl)-piperidine-1-sulfonyl]-4-phenyl-butan-2-one (93 mg;0.24 mmol), KCN (40 mg; 0.61 mmol) and (NH₄)₂CO₃(117 mg; 1.22 mmol) gave37 mg (33%) of the title compound.

[0255] LC-MS (APCI) mn/z 460.1 (MH+). ¹H-NMR (DMSO-d₆): δ10.87 (s, 1H),8.13 (s, 1H), 7.30 (m, 4H), 7.15 (m, 5H), 3.63 (m, 2H), 3.56 (d, 1H),3.41 (d, 1H), 2.87 (m, 2H), 2.61 (m, 2H), 2.39 (m, 1H), 1.92 (bt, 2H),1.83 (m, 2H), 1.63 (m, 2H).

[0256](5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonvlmethyl]-5-(3-imidazol-1-yl-propyl)-imidazolidine-2,4-dione1-[4-4(Fluorophenyl)-piperidine-1-sulfonyl]-5-imidazol-butan-2-one (75mg; 0.19 mmol), KCN (30 mg; 0.46 mmol) and (NH₄)₂CO₃ (91 mg; 0.95 mmol)was dissolved in EtOH/H₂O (1/1) (10 mL) in a sealed 22 mL tube andstirred for 17.5 h at 70° C. Another portion of KCN (40 mg; 0.61 mmol)and (NH₄)CO₃ (250 mg; 2.60 mmol) was added and the mixture was stirredat 70° C. for another 16 h. Evaporation of solvent and the residualmaterial was suspended in H₂O, precipitating crude product was removedby filtration and purified using a semipreparative HPLC system and aC-18 column with MeCN/H₂O+0.1% TFA as eluent. Fractions containing theproduct was combined and MeCN was removed by evaporation, the acidicwaterphase was made basic, pH=8-9, using 5% KHCO₃ and the precipitatingproduct was extracted using EtOAc. Organic phase dried (Na₂SO₄),filtered and evaporated to give the title compound as a colourlesssolid. Obtained 60 mg (68% yield) LC-MS (APCI) m/z 464.2 (MH+). ¹H-NMR(DMSO-d₆): δ10.75 (bs, 1H), 8.06 (s, 1H), 7.59 (s, 1H), 7.30 (m, 2H),7.16-7.08 (m, 3H), 6.88 (s, 1H), 3.95 (m, 2H), 3.60 (m, 2H), 3.47 (d,iH), 3.35 (d, 1H), 2.86 (m, 2H), 2.62 (m, 1H), 1.86-1.50 (m, 8H).

[0257](5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine-2,4-dioneCrude1-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-one(234 mg; max 0.58 mmol), KCN (151 mg; 2.3 mmol) and (NH₄)₂CO₃ (557 mg;5.8 mmol) was suspended in EtOH/H₂O (1/1) (26 mL) in a 40 mL sealedtube. The mixture was heated 70° C. and the resulting yellow solutionwas stirred for 16 h. LC/MS analysis showed that 15% unreacted ketoneremained and another portion of KCN (65 mg; 1 mmol) and (NH₄)₂CO₃ (245mg; 2.55 mmol) was added and the mixture was heated to 70° C. foranother 16 h. Solvent was removed by evaporation and the residue wastreated with H₂O (25 mL). The precipitating crude product was removed byfiltration and purified using semipreparative HPLC system and a C-18column with MeCN/H₂O+0.1 % TFA as eluent. Fractions containing theproduct was combined and MeCN was removed by evaporation, the acidicwaterphase was made basic, pH=8-9, using 5% KHCO₃ and the precipitatingproduct was filtered off, washed with water and dried in a desiccatorunder reduced pressure at 40° C. over night. This gave the titlecompound as a colourless solid. Purity >98% by NMR. Obtained 120 mg (43%yield, 2 steps). LC-MS (APCI) m/z 476.2 (MH+). ¹H-NMR (DMSO-d₆): δ10.77(s, 1H), 8.72 (d, 2H), 8.03 (s, 1H), 7.36-7.27 (m, 3H), 7.15-7.09 (m,2H), 3.60 (m, 2H), 3.50 (d, 1H), 3.34 (d, 1H), 2.92-2.80 (m, 4H), 2.62(m, 1H), 1.86-1.54 (m, 8H).

[0258] The following compounds were prepared as described in thesynthesis of(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine-2,4-dione.

[0259](5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonvlmethyl]-5-methyl-imidazolidine-2.4-dionePurificatiori not needed, after evaporation of reaction mixture andaddition of water the precipitating product was pure enough >98% by HPLC(220 nm, 254 nm) and NMR. Obtained 147 mg (71% yield, 2steps) of thetitle compound as a colorless solid. LC-MS (APCI) m/z 403.1 (MH+).¹H-NMR (DMSO-d₆): δ10.73 (bs, 1H), 8.20 (d, 1H), 8.01 (s, 1H), 7.81 (dd,1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.52 (d, 11H), 3.35 (d, 1H), 3.42-3.26(m, 2H+H₂O), 3.18-3.06 (m, 2H), 2.08-1.96 (m, 2H), 1.79-1.65 (m, 2H),1.33 (s, 3H).

[0260](5S)-5-[4-5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonxlmethyl]-5-methyl-imidazolidine2,4-dioneand(5R)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methvl-imidazolidine-2,4-dioneThe coresponding racemic material (74 mg), was dissolved in 36 mL ofisoHexane/EtOH (25/75) and separated into the pure enantiomers by usingthe following Gilson HPLC system: Column: CHIRALCEL OD, 2.0×25 cm,flow=6.0 mL/min, eluent=isoHexane/EtOH (25/75), temp=ambient, detectorUV=220 nm. The enantiomers were collected and analysed on a CHIRALCELOD-H, 0.46×25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambienttemperature, 220 nm. Rt=9.88 min. ee>99% for the faster elutingenantiomer, 29 mg (39%). Rt=11.45 min. ee=98.7% for the slower elutingenatiomer, 27 mg (36%). LC-MS (APCI) m/z 403.1 (MH+).

[0261](5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-phenethyl-imidazolidine-2,4-dione.Starting from crude1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-4-phenyl-butan-2-one(258 mg; max 0.51 mmol). Purification of crude product was made on 70 gSi-60 gel using DCM+5% MeOH as eluent. Purity >96% by NMR and HPLC (220nm, 254 nm). Obtained 201 mg (80% yield, 2 steps) of the title compoundas a colourless solid. LC-MS (APCI) m/z 493.0 (MH+). ¹H-NMR (DMSO-d₆):δ10.86 (bs, 1H), 8.21 (bd, 1H), 8.13 (s, 1H), 7.81 (dd, 1H), 7.33-7.24(m, 2H), 7.22-7.14 (m, 3H), 6.87 (d, 1H), 5.10 (m, 1H), 3.56 (d, 1H),3.42 (d, 1H), 3.43-3.28 (m, 2H+H₂O), 3.20-3.08 (m, 2H), 2.66-2.52 (m,1H), 2.45-2.31 (m, 1H), 2.08-1.96 (m, 2H), 1.96-1.83 (m, 2H), 1.81-1.65(m, 2H.

[0262](5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(3-imidazol-1yl-propyl)-imidazolidine-2,4-dioneStarting from crude1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-imidazol-1-yl-pentan-2-one(268 mg; max 0.51 mmmol). Obtained 151 mg (59% yield, 2 steps) of thetitle compound as a colourless solid. Purity >98% by NMR. LC-MS (APCI)m/z 497.2 (MH+). ¹H-NMR (DMSO-d₆): δ10.81 (bs, 1H), 8.20 (d, 1H), 8.05(s, 1H), 7.81 (dd, 1H), 7.59 (bs, 1H), 7.13 (bs, 1H), 6.88 (bs, 1H),6.87 (d, 1H), 5.08 (m, 1H), 3.47 (d, 1H), 3.40-3.28 (m, 3H+H₂O),3.17-3.06 (m, 2H), 2.07-1.95 (m, 2H), 1.79-1.64 (m, 3H), 1.61-1.48 (m,3H).

[0263](5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonvImethyl]-5-(3-pyrimidin-2-yl-propvyl-imidazolidine-2,4-dioneStarting from crude1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-one(244 mg; max 0.51 mmol). Obtained 105 mg (49% yield, 2 steps) of thetitle compound as a colourless solid. Purity >98% by NMR. ¹H-NMR(DMSO-d₆): δ10.77 (bs, 1H), 8.72 (d, 2H), 8.20 (d, 1H), 8.03 (s, 1H),7.81 (dd, 1H), 7.34 (t, 1H), 6.87 (d, 1H), 5.08 (m, 1H), 3.50 (d, 1H),;3.41-3.29 (m, 3H+H₂O), 3.16-3.07 (m, 2H), 2.83 (t, 2H), 2.06-1.96 (m,2H), 1.81-1.66 (m, 5H), 1.63-1.51 (m, 1H).

[0264](5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine-2,4-dioneand(5R)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine-2.4-dioneThe coresponding racemic material (40 mg), was dissolved in 26 mL ofisoHexane/EtOH (25/75) and separated into the pure enantiomers by usingthe same conditions as described for separation of(5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione.Rt=17.6 min. ee >99% for the faster eluting enantiomer, 17 mg (42%).Rt=21.0 min. ee =98.9% for the slower eluting enatiomer, 15 mg (37%).LC-MS (APCI) m/z 509 (MH+).

[0265]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methl]-5-ethylimidazolidine-2,4-dioneLC-MS (APCI) m/z 417 (MH+). ¹H NMR (DMSO-d₆): δ0.76 (3H, t); 1.63 (2H,q); 1.66-1.76 (2H, m); 1.96-2.06 (2H, m); 3.12 (2H, bt); 3.48, 3.35 (1Heach, ABq, J=14.9); 3.32-3.41 (2H, m); 5.04-5.12 (1H, m); 6.86 (1H, d);7.80 (1H, dd); 7.96 (1H, s); 8.19 (1H, d); 10.73 (1H, s). LC-MS (APCI)m/z 417 (MH+).

[0266]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-propylimidazolidine-2,4-dioneLC-MS (APCI) m/z 431 (MH+). ¹H NMR (DMSO-d₆): δ0.84 (3H, t); 1.03-1.16(1H, m); 1.20-1.35 (1H, m); 1.58 (2H, t); 1.65-1.77 (2H, m); 1.96-2.06(2H, m); 3.11 (2H, t); 3.21-3.42 (3H, D₂O); 3.48 (1H, half ABq, J=14.9);5.04-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 7.99 (1H, s); 8.19 (1H,d); 10.74 (1H, s).

[0267]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(2-methylpropyl)imidazolidine-2.4-dioneLC-MS (APCI) m/z 445 (MH+). ¹H NMR (DMSO-d₆): δ0.81 (3H, d); 0.88 (3H,d); 1.50-1.59 (3H, m); 1,64-1.78 (2H, m); 1.95-2.05 (2H, m); 3.06-3.16(2H, m); 3.22-3.41 (3H, D₂0); 3.46 (1H half Abq, J=15.1); 5.03-5.12 (1H,m); 6.86 (1H, d); 7.80 (1H, dd); 7.99 (1H, bs); 8.19 (1H, d); 10.71 (1H,bs).

[0268]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonvl)methyl]-5-(2-pyrimidin-2-ylethyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 495 (MH+). ¹H NMR (DMSO-d₆): δ1.66-1.78 (2H, m);1.96-2.16.(4H, m); 2.64-2.76 (1H, m); 2.84-2.95 (1H, m); 3.08-3.18 (2H,m); 3.33-3.41 (2H, m); 3.43, 3.57 (1H each, ABq, J=14.9); 5.04-5.12 (1H,m); 6.86 (1H, d); 7.34 (1 H, t); 7.80 (I1, dd); 8.12 (1H, d); 8.19 (1H,d); 8.70 (1H, d); 10.84 (1H, s).

[0269]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3-methylphenyl)methyl]imidazolidine-2,4-dioneLC-MS (APCI) m/z 493 (MH+). ¹H NMR (DMSO-d₆): δ1.66-1.78 (2H, m);1.96-2.07 (2H, m); 2.23 (3H, s); 2.84 (2H, s); 3.09-3.20 (2H, m);3.34-3.43 (2H, m); 3.45, 3.69 (1H each, ABq, J=14.7 Hz); 5.06-5.13 (1H,m); 6.87 (1H, d); 6.93-6.98 (2H, m); 7.01-7.06 (1H, m); 7.10-7.17 (1H,m); 7.81 (1H, dd); 8.08 (1H, s); 8.20 (1H, d); 10.35 (1H, s).

[0270]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(tetrahydro-2H-pyran-4-ylmethyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 487 (MH+). ¹H NMR (DMSO-d₆): δ1.06-1.26 (2H, m);1.39-1.77 (7H, m); 1.95-2.05 (2H, m); 3.06-3.27 (4H, m); 3.27-3.41 (3H,D₂O); 3.48 (1H half ABq, J=15.0 Hz); 3.69-3.79 (2H, m); 5.03-5.12 (1H,m); 6.85 (1H, d); 7.80 (1H, dd); 8.03 (1H, bs); 8.19 (1H, d); 10.79 (1H,s).

[0271]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(3-morpholin-4-ylpropyl)imidazolidine-2,4-dionetrifluoroacetic acid LC-MS (APCI) m/z 517 (MH+). ¹H NMR (DMSO-d₆):δ1.40-1.78 (6H, m); 1.96-2.06 (2H, m); 2.94-3.18 (6H, m); 3.31-3.44 (5H,m); 3.54 (1H half Abq, J=14.9 Hz); 3.60 (2H, t); 3.90-4.01 (2H, m);4.25-6.27 (1H); 6.85 (1H, d); 7.80 (1H, dd); 8.05 (1H, bs); 8.19 (1H,d); 9.52 (1H, bs); 10.88 (1H, s).

[0272]3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}propanenitrileLC-MS (APCI) m/z 442 (MH+). ¹H NMR (DMSO-d₆): δ1.66-1.78 (2H, m);1.95-2.05 (4H, m); 2.37-2.57 (2H, DMSO-d₆); 3.07-3.17 (2H, m); 3.25-3.40(2H, D₂O); 3.42, 3.52 (1H each, Abq, J=14.7); 5.04-5.12 (1H, m); 6.86(1H, d); 7.80 (1H, dd); 7.99 (1H, bs); 8.20 (1H, d); 10.91 (1H, s).

[0273] 1,1-dimethylethyl3-{4-[({4-[(5-chloronyridin-2-yl)oxy]peridin-1-yl}sulfonyl)methyl]-2.5-dioxoimidazolidin-4-yl}propylcarbamateLC-MS (APCI) m/z 547, 490 (MH+); (MH+)-tBu. ¹H NMR (DMSO-d₆): δ1.10-1.27(1H, m); 1.27-1.43 (9H, s); 1.52-1.77 (4H, m); 1.94-2.06 (2H, m);2.80-2.90 (2H, m); 3.06-3.16 (2H, m); 3.22-3.40 (4H, D₂0); 3.47 (1H halfABq, J=15.1 Hz); 5.03-5.12 (1H, m); 6.76-6.88 (2H, m); 7.80 (1H, dd);7.95 (1H, bs); 8.19 (1H, d); 10.73 (1H, bs).

[0274]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(2-morpholin-ylethyl)imidazolidine-2.4-dioneNot purified. LC-MS (APCI) m/z 502 (MH+).

[0275]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-phenylimidazolidine-2,4-dioneNot purified. LC-MS (APCI) m/z 465 (MH+).

[0276]5-[({4-[(5-chloiopyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(4-fluorophenyl)imidazolidine-2,4-dioneNot purified. LC-MS (APCI) m/z 483 (MH+).

[0277]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(1H-imidazol4-yl)imidazolidine-2,4-dioneNot purified. LC-MS (APCI) m/z 455 (MH+).

[0278]4-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin4-yl}benzamideNot purified. LC-MS (APCD m/z 508 (MH+).

[0279]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonvlmethyl]-5-[2(1H-1,2,4-triazol-1-yl)ethyl]imidazolidine-2,4-dioneNot purified. LC-MS (APCI) m/z 484 (MH+).

[0280]5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5(2-pyrimidin-2-ylethyl)imidazolidine-2.4-dioneLC-MS (APCI) m/z 462 (MH+). ¹H NMR (DMSO-d₆): δ1.62 (2H, dq); 1.77-1.86(2H, m); 2.07-2.19 (2H, m); 2.57-2.76 (2H, m); 2.81-2.96 (3H, m); 3.42,3.56 (1H each, ABq, J=14.6 Hz); 3.59-3.68 (2H, m); 7.11 (2H, t);7.27-7.36 (3H, m); 8.08 (1H, bs); 8.71 (1H, d); 10.84 (1H, bs).

[0281]5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 454 (MH+). ¹H NMR (DMSO-d₆): δ1.07-1.28 (2H, m);1.40-1.68 (7H, m); 1.77-1.85 (2H, m); 2.56-2.67 (1H, m); 2.85 (2H, dq);3.22 (2H, dq); 3.39-3.45 (1H, m); 3.48 (1H half ABq, J=14.5 Hz);3.53-3.66 (2H, m); 3.75 (2H, dt); 7.11 (2H, t); 7.26-7.33 (2H, m); 8.00(1H, bs); 10.68 (1H, bs).

[0282]4-[4-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-2,5-dioxoimidazolidin4-yl]benzamideLC-MS (APCI) m/z 475 (MH+). ¹H NMR (DMSO-d₆): δ1.61 (2H, dq); 1.77-1.88(2H, m); 2.58-2.69 (1H, m); 2.85-3.01 (2H, m); 3.60 (1H half ABq, J=14.6Hz); 3.60-3.69 (2H, m); 7.12 (2H, t); 7.26-7.34 (2H, m); 7.42 (1H, bs);7.65 (2H, d); 7.91 (2H, d); 8.01 (1H, bs); 8.85 (1H, s); 10.95 (1H, bs).

[0283]5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(1H-imidazol4-yl)imidazolidine-2,4-dioneNot purified.

[0284] LC-MS (APCI) m/z 422 (MH+).

[0285]5-({[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 470 (MH+). ¹H NMR (DMSO-d₆): δ1.07-1.28 (2H, m);1.40-1.68 (7H, m); 1.76-1.85 (2H, m); 2.56-2.68 (1H, m); 2.85 (2H, q);3.22 (2H, q); 3.48 (1H half ABq, J=14.5 Hz); 3.53-3.67 (2H, m); 3.75(2H, t); 7.26-7.37 (4H, m); 8.02 (1H, bs); 10.79 (1H, bs).

[0286] 5-({[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(3-morpholin-4-ylpropyl)imidazolidine-2,4-dionetrifluoroacetic acid LC-MS (APCI) m/z 499 (MH+). ¹H4 NMR (DMSO-d₆):δ1.41-1.87 (8 H, m); 2.56-2.69 (1H, m); 2.86 (2H, q); 2.95-3.14 (4H, m);3.33-3.44 (3H, m); 3.52 (1H half ABq, J=14.6 Hz); 3.55-3.69 (4H, m);3.90-4.00 (2H, m); 7.25-7.37 (4H, m); 8.07 (1H,.s); 9.89 (1H, bs); 10.87(1H, s).

[0287](5R,S)-5-Methyl-5-[({4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-yl}sulfonyl)methyl]imidazolidine-2,4-dioneLC-MS (APCI) m/z 422.1 (MH+). Purity >95% by NMR. ¹H-NMR (DMSO-d₆):δ10.75 (1H, s); 8.44 (1H, d); 8.02 (1H, s); 7.85 (1H, dd); 7.03 (1H, d);3.75 (4H, m); 3.55 (1H, d); 3.35 (1H, d); 3.21 (4H, m); 1.31 (3H, s).

[0288]6-(4-{[({4R,S}4-methyl-2,5-dioxoimidazolidin4-yl)methyl]sulfonyl}piperazin-1-yl)piperidine-3-carbonitrilLC-MS (APCI) m/z 379.1 (MH+). Purity >99% by NMRP ¹H-NMR (DMSO-d₆):δ10.74 (1H, s); 8.52 (1H, d); 8.00 (1H, s); 7.90 (1H, dd); 7.00 (1H, d);3.78 (4H, m); 3.55 (1H, d); 3.36 (1H, d); 3.20 (4H, m); 1.31 (3H, s).

[0289](5R,S)-5-({[4-(4-fluorophenyl)piperazine-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 371.1 (MH+). Purity >98% by NMR. ¹H-NMR (DMSO-d₆):δ10.75 (1H, s); 8.03 (1H, s); 7.11-6.95 (4H, m); 3.56 (1H, d); 3.36 (1H,d); 3.25 (4H, m); 3.15 (4H, m); 1.33 (3H, s).

[0290](5R,S)-5-[({4-[(4-fluorophenyl)methyl]piperazine-1-yl}sulfonyl)methyl]-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 385.1 (MH+). Purity >95% by NMR. ¹H-NMR (DMSO-d₆):δ10.72 (1H, s); 7.99 (1H, s); 7.33 (2H, m); 7.15 (2H, m); 3.50 (2H, s);3.49 (1H, d); 3.30 (1H, d); 3.12 (4H, m); 2.42 (4H, m); 1.32 (3H, s).

[0291](5R,S)-5-methyl-5-{[(4-pyrimidin-2-ylpiperazine-1-yl)sulfonyl]methyl}imidazolidine-2,4-dione.LC-MS (APCI) m/z 355.1 (MH+). Purity >99% by NMR. ¹H-NMR (DMSO-d₆):δ10.74 (1H, s); 8.40 (2H, d); 8.01 (1H, s); 6.68 (1H, t); 3.83 (4H, m);3.53 (1H, d); 3.33 (1H, d); 3.18 (4H, m); 1.31 (3H, s).

[0292]5-(3-aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]imidazolidine-2,4-dionetrifluoroacetic acid 1,1-dimethylethyl3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}propylcarbamate(426 mg, 0.78 mmol) was dissolved in 10 mL CH₂Cl₂ and 4 mL of TFA wasadded. The reaction was stirred at rt for 1 hour. The solvent wasremoved to give 408 mg (93%) of the title compound as a white solid.LC-MS (APCI) m/z 446 (ME+). ¹H NMR (CD₃0D): δ1.48-1.63 (1H, m);1.69-1.96 (5H, m); 2.01-2.12 (2H, m); 2.93 (2H, t); 3.20-3.29 (2H, m);3.40, 3.60 (1H each ABq, J=14.6 Hz); 3.44-3.54 (2H, m); 4.85 (4H, D₂O);5.14-5.22 (1H, m); 6.78 (1H, d); 7.67 (IfH, dd); 8.08 (1H, d).

[0293]5-[4(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-piperidin4-yl-imidazolidine-2,4-dionhydro chloride4-{4-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-2,5-dioxo-imidazolidin-4-yl}-piperidine-1-carboxylicacid tert-butyl ester (100 mg, 0.16 mmol) was solved in 2 M hydrogenchloride (ethyl acetate, 30 ml) and methanol (5 ml). The solution wasstirred at 50° C. for 1 hour. Evaporation afforded 90.5 mg (0.16 mmol)of the title compound5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-piperidin4-yl-imidazolidine-2,4-dionhydro chloride in quantitative yield. LC-MS (APCI) m/z 472.3 (MH+). ¹HNMR (DMSO-d₆): δ10.88 (1H, s); 9.05 (1H, d); 8.48 (1H,m); 8.21 (1H, d);7.82 (1H, dd); 6.87 1H, d); 5.10 1H, m); 3.47 (2H, s); 3.43-3.13 (7H,m); 2.78 (2H, m); 2.02-1.39 (9H, m).

[0294]4-{4-[4-5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-2,5-dioxo-imidazolidin4-yl}-piperidine-1-carboxylicacid tert-butyl ester For preparation of the reacting ester,piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester, sefor example Albert A Carr et al, Journal of Organic Chemistry (1990),55(4), 1399-401. LC-MS (APCI) m/z 472.3 (MH+-Boc).

[0295]5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(tetrahvdo-pyran-4-yl)-2,4-dionLC-MS (APCI) m/z 403.2 (MH+). ¹H NMR (DMSO-d₆): δ10.77 (1H,s); 8.20 (1H,d); 8.19 (1H,s); 7.81 (1H, dd); 6.87 (1H, d); 5.09 (1H, m); 3.88 (2H,t); 3.45 (2H, s); 3.38 (2H, m); 3.21 (2H, t); 3.13 (2H, m); 2.02 (2H,m); 1.84 (1H, t); 1.72 (2H, m); 1.60 (1H, d); 1.32 (4H, m).

[0296]5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-pyridin-4-yl-imidazolidine-2,4-diontrifluoroacetic acid LC-MS (APCI) m/z 466.2 (MH+). ¹H NMR (DMSO-d₆):δ11.15 (1H, s); 8.97 (1H, s); 8.76 (2H, d); 8.20 (1H, d); 7.82 (2H, dd);7.80 (1H, d); 6.86 (1H, d); 5.10 (1H, m); 4.17 (1H, m); 3.73 (1H, d);3.41 (2H, m); 3.17 (2H, m); 2.08 (2H, m); 1.72 (2H, m).

[0297] 1,1-dimethylethyl4-({4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}methyl)piperidine-1-carboxylateThe title compound was prepared essentially as described in thesynthesis of(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 530 (MH+ -boc). ¹H NMR (DMSO-d₆): δ0.88-1.10 (2H, m);1.30-1.77 (16H, m); 1.94-2.06 (2H, m); 2.53-2.77 (2H, m); 3.05-3.17 (2H,m); 3.21-3.41 (4H, D₂0); 3.48 (1H half ABq, J=14.7 Hz); 3.73-3.88 (2H,m); 5.03-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 8.04 (1H, bs); 8.19(1H, d); 10.55 (1H, bs).

[0298]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(piperidin-4-ylmethyl)imidazolidine-24-dionetrifluoroacetate The title compound was prepared as described in thesynthesis of5-(3-aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]imidazolidine-2,4-dionetrifluoroacetic acid. LC-MS (APCI) m/z 486 (MH+). ¹H NMR (DMSO-d₆):δ1.17-1.40 (2H, m); 1.47-1.81 (7H, m); 1.94-2.07 (2H, m); 2.75-2.93 (2H,m); 3.06-3.42 (7H, m); 3.50 (1H half ABq, J=15.6 Hz); 5.04-5.12 (1H, m);6.85 (1H, d); 7.80 (1H, dd); 8.06 (1H, s); 8.08-8.22 (2H, m); 8.45 (1H,bd); 10.85 (1H, s).

[0299]N-(3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin4-yl}propvl)methanesulfonamide5-(3-Aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]imidazolidine-2,4-dionetrifluoroacetic acid (100 mg, 0.1 8 mmol) was slurried in 2 mL DCM.DIPEA (62 μL, 0.36 mmol) was added and the slurry was stirred for someminutes. Sulfonylchloride (16 μL, 0.18 mmol) was added and the reactionwas stirred at rt over night. The crude product was purified bypreparative HPLC. LC-MS (APCI) mn/z 524 (MH+). ¹H NMR (DMSO-d₆):δ1.19-1.52 (2H, m); 1.58-1.77 (4H, m); 1.95-2.06 (2H, m); 2.85 (3H, s);2.83-2.93 (2H, m); 3.12 (2H, t); 3.19-3.46 (3H, D₂0); 3.50 (1H half ABq,J=15.7 Hz); 5.04-5.12 (1H, m); 6.86 (1H, d); 6.97 (1H, t); 7.80 (1H,dd); 8.01 (1H, s); 8.19 (1H, d); 10.79 (1H, s).

EXAMPLE 9(5R,S)-5-[4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine-2.4-dione

[0300]

[0301]1-([4-(5-Chloro-2-pyridinyl)-1-piperazinyl]sulfonyl)-5-(2-pyrimidinyl)-2-pentanone(0.397 g, 0.936 mmol), potassium cyanide (0.122 g, 1.87 mmol), ammoniumcarbonate (0.500 g, 4.68 mmol) and 50% ethanol (4 mL) were stirred in asealed vial at 75° C. (oil temp) for 17 hours. The ethanol was removedby rotary evaporation, pH was adjusted to 6 with 1M HCl, the suspensionwas filtered, the solid was washed with a little water, collected anddried in vacuo at 45° C. Some more product was recovered from theaqueous filtrate by adding solid sodium chloride to saturation andextracting the mixture with acetonitrile (2×10 mL). Drying with Na₂SO₄,filtering and concentrating the organic phase gave a second crop. Thecombined crops were dissolved in tetrahydrofuran (5-10 mL), adsorbed onsilica. (3 g) and applied on a short silica column. Elution with EtOAcfollowed by EtOAc-MeCN (1:1) gave 0.30 g (65% yield) of the titlecompound as a white crystalline solid. LC-MS (APCI) m/z 494 (MH+). ¹HNMR (DMSO-d₆) δ10.78 (1H, bs); 8.70 (2H, d, J=5Hz); 8.13 (1H, d, J=3Hz);8.02 (1H, s); 7.63 (1H, dd, J₁=3Hz, J₂=9 Hz); 7.33 (1H, t, J=5 Hz); 6.93(1H, d, J=10 Hz); 3.63-3.56 (4H, m); 3.52 (1H, d, J=14 Hz); 3.34 (1H, d,J=14 Hz; obscured by water signal), 3.24-3.14 (4H, m); 2.82 (2H, t, J=7Hz) and 1.79-1.50 (4H, m's). ¹³C NMR (DMSO-d₆) δ175.6, 169.5, 157.2,157.0, 156.5, 145.6, 137.3, 119.2, 119.1, 108.8, 62.4, 52.7, 44.5, 38.2,36.4 and 21.2.

[0302] The starting materials were prepared as follows:

[0303]1-([4-(5-Chloro-2-pyridinyl)-1-piperazinyl]sulfonyl)-5-(2-pyrimidinyl)-2-pentanone

[0304] A stirred solution of 1-(5-Chloro-2-pyridinyl)-1-methylsulfonylpiperazine (0.64 g, 2.32 mmol) in dry THF (25 mL, 40 rel vol), undernitrogen, was cooled-to −10° C. causing the sulfonamide to precipitateout of solution. LHMDS 1M in THF (4.64 mL, 4.64 mmol) was addeddropwise, over 4 min, to the suspension of sulfonamide, the mixture wasthen stirred for 40 min. 4-(2-Pyriridinyl)-butyric acid ethyl ester(0.68 g, 3.48 mmol) (example 8 ) in dry THF (6.4 mL, 10 rel vol) wasadded dropwise, over 4 min, and the mixture stirred for 30 min. Themixture was quenched with saturated NH4CI (0.64 mL, 1 rel vol) andevaporated to a semi-solid residue. The residue was taken up in DCM (20rel vol) and the organic layer was washed with water (15 mL, 24 relvol), brine (15 mL, 24 rel vol), and dried with MgSO₄. Removal of thesolvent by rotary evaporation gave the crude product as an off whitesolid (0.84 g, 85%). The crude product was purified by Biotage FLASHchromatography, using ethyl acetate/isohexane (90:10) as eluant, to givepure ketone as a white amorphous solid.

[0305] 1-(5-Chloro-2-pyridinyl)-1-methylsulfonyl piperazine To asolution containing 1-(5-Chloro-2-pyridinyl)-piperazine (1 eq.) intoluene (25 volumes) is added triethylamine (1.1 eq), and the mixture iscooled down to 5° C. in an ice bath. Methanesulfonyl chloride dilutedwith toluene (0.5 vols) is slowly added to the cooled solution, keepingthe temperature below 10° C. Once the addition is finished, the reactionis allowed to warm-up to room temperature. Water (6.6 vols) is added andthe mixture is filtered and cake slurried in Toluene (2 vols). The cakeis then washed with Toluene (2 vols) and dried in a vacuum oven at 40°C. overnight.

[0306] 1-(5-Chloro-2-pyridinyl)-piperazine

[0307] Piperazine (4 eq) is charged in the reaction vessel as a solid.At room temperature pyridine (1.43 vols) is added to the vessel followedby toluene (2.14 vols). The final slurry is stirred and heated to refluxat 120° C. to obtain a complete solution. To a separate vessel charge2,5-dichloropyridine (DCP) followed by Toluene (1.43 vols) to dissolvethe solid. The dissolution is endothermic, and it is necessary to warmup the solution to ˜30° C. to get complete solution. The solutioncontaining DCP is then slowly discharged into the reaction vessel over 5hours. At this point the remaining amount of DCP should be about 20%.The reaction is left refluxing overnight to reach completion. Thereaction mixture is allowed to cool to room temperature, then water isadded (6 vols). The two layers are separated, and the aqueous phase isre-extracted with Toluene (5 vols). The two organic layers are combinedand re-washed with H₂O (6 vols). Finally, the organic layer is washedwith brine (6 vols).

[0308](5S)-5-[4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-Propyl)-imidazolidine-2,4-dioneand(5R)-5-[4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine2,4-dioneThe coresponding racemic material (23 mg) was dissolved in 8 mL ofisoHexane/EtOH (25/75) and separated into the pure enantiomers by usingthe following Gilson HPLC system: Column: CHIRALCEL OD, 2.0×25 cm,flow=6.0 mL/min, eluent=isoHexane/EtOH (25/75), temp=ambient, detectorWV=230 nm. The enantiomers were collected and analysed on a CHIRALCELOD-H, 0.46×25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambienttemperature, 220 nm. Rt=11.5 min. ee >99% for the faster elutingenantiomer, 8.7 mg (37%). LC-MS (APCI) m/z 494.1 (MH+). [α]_(D)=−26.4°(c=0.0022 g/mL, EtOH, t=20° C.) Rt=14.5 min. ee=98 % for the slowereluting enatiomer, 9 mg (39%). LC-MS (APCI) m/z 494.1 (MH+).[α]_(D)=+24.5° (c=0.0026 g/mL, EtOH, t=20° C.)

EXAMPLE 10

[0309] The following compounds were prepared using a method analogous tothat described in Example 8 or 9. 5-[4-(4-Chloro-phenyl)-piperazine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl]- imidazolidine-2,4-dione

m/z 493 (MH+) 5-[4-(4-Fluoro-phenyl)-piperazine-1-sulfonylmethyl]-5-[2-(5-fluoro-pyrimidin-2-yl)-ethyl]-imidazolidine-2,4-dione

m/z 481 (MH+) 5-[4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-[2-(5-fluoro-pyrimidin-2-yl-ethyl]-imidazolidine-2,4-dione

m/z 498 (MH+) 5-[4-(3,4-Dichloro-phenyl)-piperazine-1-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl]- imidazolidine-2,4-dione

m/z 527 (MH+)

EXAMPLE 11

[0310] Compounds with the general formula

[0311] were synthesised according to the method described in Example 8KETONE INTERMEDIATES R R2 z Analysis⁽¹⁾

Me S GC/MS m/z 242 (M⁺)

Me S GC/MS m/z 267 (M⁺)

Me S GC/MS m/z 326 (M⁺)

Me SO2 LC/MS m/z 275 (MH+)

Me SO2 —

[0312] 1-(1,1′-biphenyl-4-ylthio)propan-2-one1-[(4-bromophenyl)thio]propan-2-one (357 mg, 1.46 mmol) was treated withphenyl boronic acid (231 mg, 1.89 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (II) complexwith dichloromethane (1:1) (36 mg), toluene (20 ml), methanol (7.5 ml),saturated sodium carbonate solution (3.5 ml) and were stirred togetherat 80° C. for 18 hours. After cooling the reaction mixture was treatedwith dilute hydrochloric acid and extracted into ethyl acetate. Theproduct was purified by flash chromatography on silica, eluting with 25%ethyl acetate:iso-hexane to give 277 mg product. GC/MS m/z: 242 [M⁺]. ¹HNMR (CDCl₃): δ2.33 (3H, s); 3.73 (2H, s); 7.37 (1H, s); 7.42-7.48 (4H,m); 7.54-7.59 (4H, m).

[0313] The following compounds were prepared as described in thesynthesis of 1-(1,1′-biphenyl-4-ylthio)propan-2-one

[0314] 4′-[(2-oxopropyl)thio]-1,1′-biphenyl4-carbonitrile GC/MS m/z: 267[M+]. ¹H NMR (CDCl₃): δ2.34 (3H, s); 3.75 (2H, s); 7.44, 7.54 (4H, abq,J=8.5 Hz); 7.67, 7.74 (4H, abq, J=8.5 Hz).

[0315]1-({4′-[(trifluoromethyl)oxy]-1,1′-biphenyl-4-yl}thio)propan-2-one GC/MSm/z: 326 [M+]. ¹H NMR (CDCl₃): δ2.34 (3H, s); 3.73 (2H, s); 7.30 (2H,d); 7.43 (2H, d); 7.51 (2H, d); 7.58 (2H, d).

[0316] 1-(1,1′-biphenyl4-ylsulfonyl)propan-2-one1-(1,1′-biphenyl-4-ylthio)propan-2-one (69 mg, 0.28 mmol) was stirred atroom temperature with sodium bicarbonate (72 mg, 0.85 mmol), oxone ((525mg, 0.85 mmol), water (5 ml) and methanol (lOml) for 3 hours. Water (50ml) was added and the product extracted into ethyl. acetate (3×25 ml).The extracts were brine washed, sodium sulphate dried and evaporated togive 78 mg (99%) product that was of sufficient purity to use with outfurther purification. LC-MS (APCI) m/z 275 (MH+). ¹H NMR (CDCl₃): δ2.47(3H, s); 4.22 (2H, s); 7.44-7.54 (3H, m); 7.64 (2H, d); 7.80, 7.97 (4H,abq, J=8.6 Hz).

[0317] 4′-[(2-oxopropyl)sulfonyl]-1,1′-biphenyl-4-carbonitrile The titlecompound was prepared as described in the synthesis of1-(1,1′-biphenyl-4-ylsulfonyl)propan-2-one. ¹H NMR (DMSO-d₆): δ2.48 (3H,s); 4.23 (2H, s); 7.74 (2H, d); 7.81 (4H, t); 8.02 (2H, d).

HYDANTOINS OF FORMULA I

[0318] The following compounds were prepared as described in thesynthesis of(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione(Example 8 ). R R2 z Analysis⁽¹⁾

Me SO2 m/z 396 (MH+)

Me S(O) m/z 413 (MH+)

Me SO2 m/z 345 (MH+)

Me SO2 m/z 370 (MH+)

[0319](5R,S)-[4-(5-Chloro-pyridin-2-yloxy)-benzenesulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 396 (MH+). ¹H NMR (DMSO-d₆): δ1.27 (3H, s); 3.71, 3.78(1H each, ABq, J=15.0); 7.23 (1H, d); 7.36-7.41 (2H, m); 7.82-7.87 (3H,m); 8.04 (1H, dd); 8.27 (1H, d); 10.79 (1H, s).

[0320] 5-chloro-2-{[4-(methylsulfonyl)phenyl]oxy}pyridine2,5-dichloropyridine (1.48 g; 10 mmol), 4-methylsulfonylphenol (1.89 g;11 mmol) and Cs₂CO₃ (4.24 g; 13 mmol) was slurried in 75 mL of NMP. Theslurry was heated to approx 170° C. over night. After cooling the Cs₂CO₃was filtered off and the solvent was extracted between H₂O and EtOAc.The organic phase was dried over Na₂SO₄ and evaporated. Heptane:EtOAc2:1 was added to the residue and the crystalls was filtered off 1.42 g(50%). LC-MS(APCI) m/z 284 (MH+). ¹H NMR CDCl₃: δ3.09 (3H, s); 7.02 (1H,d); 7.33 (2H, d); 7.76 (1H, dd); 8.00 (2H, d); 8.17 (1H, s).

[0321]5-methyl-5-[({4′-[(trifluoromethyl)oxy]-1,1′-biphenyl-4-yl}sulfinvl)methyl]imidazolidine-2,4-dione5-methyl-5-[({4′-[(trifluoromethyl)oxy]-1,1′-biphenyl-4-yl}thio)methyl]iimidazolidine-2,4-dione (48 mg, 0.112 mmol) was stirred atroom temperature with oxone (50 mg), sodium bicarbonate (50 mg), water(5 ml) and Methanol (10 ml) for 18 hours. The solid was filtered off andcrystalissed from ethanol to give 20 mg of the title compound.LC-MS(APCI) m/z very weak 413 (MH+). ¹H NMR (DMSO-d₆): δ1.41 (3H, s);3.04-3.27 (2H, m); 7.47 (2H, d); 7.67-7.73 (2H, m); 7.78-7.90 (5H, m);8.21 and 8.37 (1H, 2 s); 10.79 and 10.91 (1H, 2 s)

[0322]5-methyl-5-[({4′-[(trifluoromethyl)oxy]-1,1′-biphenyl-4-yl}thio)methyl]imidazolidine-2,4-dioneLC-MS(APCI) m/z very weak 397 (MH+). ¹H NMR (DMSO-d₆): δ1.33 (3H, s);3.29 (2H, s); 7.42-7.45 (4H, m); 7.61 (2H, d); 7.77 (2H, d); 7.99 (1H,s); 10.75 (1H, s).

[0323]5-[(1,1′-biphenyl-4-ylsulfonyl)methyl]-5-methylimidazolidine-2,4-dioneLC-MS(APCI) m/z 345 (MH+). ¹H NMR (DMSO-d₆): δ1.27 (3H, s); 3.72, 3.81(2H, abq, J=15.3 Hz); 7.45 (1H, t); 7.52 (2H, t); 7.76 (2H, d); 7.82(1H, s); 7.88, 7.94 (4H, abq, J=8.9 Hz); 10.80 (1H, bs).

[0324]4′-{[(4-methyl-2.5-dioxoimidazolidin-4-yl)methyl]sulfonyl}-1,1′-biphenyl4-carbonitrileLC-MS(APCI) m/z very weak 370 (MH+). ¹H NMR (DMSO-d₆): δ1.26 (3H, s);3.74, 3.84 (2H, abq, J=16.0 Hz); 7.81 (1H, s); 7.91-8.03 (8 H, m); 10.81(1H, s).

EXAMPLE 12 Synthesis of Enantiomeric Pure Hydantoins

[0325]

[0326] Representative synthetic route is shown overleaf.

[0327] Reagents and conditions: a) KCN, NH₄CO₃, EtOH/H₂O, +90° C., 3 h.b) Chiral separation, CHIRALPAK AD, Methanol as eluent. c) Cl₂ (g),AcOH/H₂O, <+15° C., 25 min. d) Diisopropylethylamine, THF. −20° C., 30min.

[0328] Experimental procedures

[0329](5S)-5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione4-(4-Fluorophenyl)piperidine hydrochloride (63 mg, 0.29 mmol) was takenup in 3 mL of dry THF, neutralized with diisopropylethylamine (50 μL,0.29 mmol) and cooled on an ice-water bath.[(4S)-4-metyl-2,5-dioxo-imidazolodin-4-yl]methanesulfonyt chloride (80mg, 0.35 mmol) was added and after stirring for 10 min,diisopropylethylamine (50 μL, 0.29 mmol) was added and the reactionmixture was stirred at ambient temperature until LC-MS (APCD) indicatedconsumption of the amine. The reaction mixture was evaporated and theresidue taken up in EtOH and heated to 50° C. and allowed to cool beforewater was added. The precipitated product was collected and washed withEtOH/water and dried in vacuum to yield 87 mg. LC-MS (APCI) m/z 370(MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1 H, s); 7.29.(2 H, dd);7.11 (2 H, dd); 3.61 (2 H, dd); 3.50, 3.33 (1 H each, ABq, J=14.7 Hz);2.91-2.80 (2 H,m); 2.67-2.57 (1 H, m); 1.82 (2 H, d); 1.62 (2 H, ddd);1.33 (3 H, s).

[0330] The starting materials were prepared as follows:

[0331] 5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4dione Asteel vessel was charged with ethanol and water (315 mL/135mL). 31.7 g(0.175 mol) of benzylthioacetone, 22.9 g (0.351 mol) of potassiumcyanide and 84.5 g (0.879 mol) of ammonium carbonate was added. Theclosed reaction vessel was kept in an is oil bath (bath temperature-90IC) under vigorous stirring for 3 h. The reaction vessel was cooled withice-water (0.5 h), the yellowish slurry was evaporated to dryness andthe solid residue partitioned between 400 mL water and 700 mLethylacetate and separated. The water-phase was extracted withethylacetate (300 mL). The combined organic phases were washed withsaturated brine (150 mL), dried (Na₂SO₄), filtered and evaporated todryness. If the product did not crystallize, 300 mL of dichloromethanewas added to the oil. Evaporation gave the product as a slightlyyellowish powder,43.8 g (90%). LC-MS (APCI) m/z 251.1 (MH+). ¹H NMR(DMSO-d₆): δ10.74 (1H,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s);2.72, 2.62 (1H each, ABq, J=14.0 Hz);. 1.29 (3H, s). ¹³C NMR (DMSO-d₆):δ177.30, 156.38, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96, 36.39,23.15.

[0332](5S)-5-methyl-5-{[(phenylmethyl)thio]methyl}imiidazolidine-2,4-dione Thetitle compound was prepared by chiral separation of the racemic materialusing a 250 mm×50 mm column on a Dynamic Axial Compression PreparativeHPLC system. The stationary phase used was CHIRALPAK AD,eluent=Methanol, flow=89 mL/min, temp=ambient, UV=220nm, sample conc=150mg/mL, injection volume=20mL. Retention time for title compound=6 min.Analysis of chiral purity was made using a 250 mm×4.6 mm CHIRALPAK-ADcolumn from Daicel, flow=0.5 mL/min, eluent=Ethanol, UV=220 nm,temp=ambient. Retention time for title compound=9.27 min. Purityestimated to >99% ee. LC-MS (APCI) m/z 251.1 (MH+). [α]_(D)=−30.3°(c=0.01 g/mL, MeOH, T=20° C.). ¹H NMR (DMSO-d₆): δ10.74 (1H,s); 8.00(1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq,J=14.0 Hz); 1.29 (3H, s). ¹³C NMR (DMSO-d₆) δ: 177.30, 156.28, 138.11,128.74, 128.24, 126.77, 62.93, 37.96, 36.39, 23.15.

[0333](5R)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione Thetitle compound was prepared by chiral separation of the racemic materialusing a 250 mm×50 mm column on a Dynamic Axial Compression PreparativeHPLC system. The stationary phase used was CHIRALPAK AD,eluentPMethanol, flow=89 mL/min, temp=ambient, UV=220 nm, sampleconc=150 mg/mL, injection volume=20 mL. Retention time for titlecompound=10 min. Analysis of chiral purity was made using a 250 mm×4.6mm CHIRALPAK-AD column from Daicel, flow=0.5 mL/min, eluentPEthanol,UV=220 nm, temp=ambient. Retention time for title compound=17.81 min.Chiral purity estimated to >99% ee. LC-MS (APCI) m/z 251.0 (MH+).[α]_(D)=+30.3° (c=0.01 g/mL, MeOH, T=20° C.). ¹H NMR (DMSO-d₆) δ: 10.74(1H,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1Heach, ABq, J=14.0 Hz); 1.29 (3H, s). ¹³C NMR(DMSO-d₆) δ: 177.31, 156.30,138.11, 128.74, 128.25, 126.77, 62.94, 37.97, 36.40, 23.16.

[0334] [(4S)-4-methyl-2,5-dioxoimidazolidin4-yl]methanesulfonyl chloride(5S)-5-methyl-5- {[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione(42.6 g; 0.17 mol) was dissolved in a mixture of AcOH (450 mL) and H₂O(50 mL). The mixture was immersed in an ice/water bath, Cl₂ (g) wasbubbled through the solution, the flow of gas was adjusted so that thetemperature was kept below +15° C. After 25 min the solution becameyellow-green in colour and a sample was withdrawn for LC/MS and HPLCanalysis. It showed that starting material was consumed. The yellowclear solution was stirred for 30 min and an opaque solution/slurry wasformed. The solvent was removed on a rotary evaporator using waterbathwith temperature held at +37° C. The yellowish solid was suspended inToluene (400 mL) and solvent removed on the same rotary evaporator. Thiswas repeated once more. The crude product was then suspended iniso-Hexane (400 mL) and warmed to +40° C. while stirring, the slurry wasallowed to cool to room temperature before the insoluble product wasremoved by filtration, washed with iso-Hexane (6×100 mL), and driedunder reduced preassure at +50° C. over night. This gave the product asa slightly yellow powder. Obtained 36.9 g (95%) of the title compound.Purity by HPLC =99%, NMR supported that purity. [α]_(D)=−12.4° (c=0.01g/mL, THF, T=20° C.). ¹H NMR (THF-d₈): δ9.91 (1H, bs); 7.57 (1H, s);4.53, 4.44 (1H each, ABq, J=14.6 Hz); 1.52 (s, 3H, CH₃). ¹³C NMR(THF-d₈): δ174.96; 155.86; 70.96; 61.04; 23.66.

[0335] [(4R)4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chlorideFollowing the procedure described for[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride.Starting from(5R)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione(10.0 g, 40 mmol). Obtained 8.78 g (96% yield) of the title compound.Purity by NMR >98%. [α]_(D)=+12.80 (c=0.01 g/mL, THF, T=20° C.). ¹H NMR(THF-d₈): δ9.91 (1H, brs); 7.57 (1H, s); 4.53, 4.44 (1H each, ABq,J=14.6 Hz); 1.52 (s, 3H, CH₃). ¹³C NMR (THF-d₈): δ174.96; 155.84; 70.97;61.04; 23.66.

EXAMPLE 13

[0336] Compounds with the general formula

[0337] were synthesised according to the method described in Example 12.AMINE INTERMEDIATES Amine Analysis

m/z 246 (MH+); ¹H NMR data

m/z 185 (MH+); ¹H NMR data

m/z 198 (MH+); ¹H NMR data

m/z 218/220 3:1 (MH+); ¹H NMR data

m/z 247 (MH+); ¹H NMR data

m/z 204 (MH+); ¹H NMR data

¹H NMR data

¹H NMR data

¹H NMR data

¹H NMR data

¹H NMR data

¹H NMR data

m/z 225 (MH+)

m/z 240 (MH+)

m/z 235 (MH+)

m/z 203 (MH+)

m/z 208 (MH+)

m/z 262 (MH+)

m/z 214 (MH+)

m/z 212 (MH+)

m/z 203 (MH+)

m/z 208 (MH+)

m/z 246 (MH+)

m/z 214 (MH+)

m/z 235 (MH+)

m/z 220 (MH+)

m/z 220 (MH+)

m/z 197 (MH+); ¹H NMR data

m/z 285 (MH+)

m/z 195 (MH+); ¹H NMR data

m/z 257, 259 (MH+)

m/z 258 (MH+)

m/z 270 (MH+)

m/z 274, 276 (MH+)

m/z 324 (MH+)

m/z 230 (MH+)

m/z 229 (MH+)

m/z 241 (MH+)

m/z 265 (MH+)

[0338] All other amines used are commercially available or earlierdescribed.

[0339] 4-{4-[(trifluoromethyl)oxy]phenyl)piperidine trifluoroacetic acidPd(PPh₃)₄ (87 mg, 0.0075 mmol), LiCl (190 mg, 4.5 mmol), tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate(0.50 g 1.5 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.43 g, 2.1mmol) and aq Na₂CO₃ (2 mL, 2N solution) were mixed in 5.2 mL DME andheated at 85° C. for 3 h followed by cooling to room temperature andconcentrated under reduced pressure. The residure was partitionedbetween DCM (10 mL), aq Na₂CO₃ (10 mL, 2N solution) and conc NH₄OH (0.6mL). The layers were separated and the aqueous layer extracted with DCM(3×10 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated. Purification by column chromatography (SiO₂,Heptane/Ethylacetate/DCM 5:1:1) gave tert-butyl4-[4-(trifluoromethoxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate(0.27 g, 52%). The product and 5% Pd/C (30 mg) was mixed in MeOH (3 mL)and stirred under H₂ (1 atm) for 24 h. The mixture was filtered throughCelite and concentrated to give tert-butyl4-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate (0.23 g, 86%).The crude product was dissolved in a mixture of TFA (2 mL) and DCM (4mL) and stirred at RT for 2 h. The reaction mixture was concentrated andpurified by preparative HPLC to give the title compound (0.14 g, 58%,three steps 26%). LC-MS (APCI) m/z 246 (MH+). ¹H NMR (CDCl₃): δ9.38 (1H, bs); 8.97 (1 H, bs); 7.26 (2 H, d); 7.20 (2 H, d); 3.60 (2 H, bd);3.07 (2 H, q); 2.88-2.72 (1H, m); 2.18-2.01 (4 H, m). ¹⁹F NMR (CDCl₃):δ−58.35 (3F), −76.19 (3F).

[0340] 4-[(4-chlorophenyl)ethynyl]-1,2,3,6-tetrahydropyridinehydrochloride PdCl₂(PPh₃)₂ (47 mg, 0.07 mmol) and CuI (13 mg, 0.07 mmol)were dissolved in Et₃N (2.7 mL) and THF (8.4 mL) under a stream of argonand stirred for 10 min. A solution of tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate(0.46 g 1.4 mmol) and 2-ethynylpyridine (152 μL, 1.5 mmol) in 3.5 mL THFwas added. The reaction mixture was stirred at RT for 2 h, diethyl etherwas added and the precipitate was filtered off. The clear solution waswashed with saturated aqueous NH₄Cl, water, Brine and dried (Na₂SO₄).Concentration and purification by column chromatography (SiO₂,Heptane/Diethyl ether 1:2) gave tert-butyl4-[(4-chlorophenyl)ethynyl]-3,6-dihydropyridine-1(2H)-carboxylate (0.26g, 58%). The product was dissolved in THF (3 mL) and conc HCl (3 mL) andstirred at RT for 30 min. Concentration several times with toluene andEtOH gave the title compound (0.20 g, 98%, two steps 57%). LC-MS (APCI)m/z 218/220 3:1 (MH+). ¹H NMR (DMSO-d₆): δ9.25 (2 H, bs); 7.49-7.44 (4H. m); 6.24-6.11 (1 H, m); 3.75-3.63 (2 H, m); 3.25-3.15 (2 H, m);2.48-2.42 (2 H, m).

[0341] The following amines were prepared in a similar way asdescibedfor 4-[(4-chlorophenyl)ethynyl]-1,2,3,6-tetrahydropyridinehydrochloride.

[0342] 2-(1,2,3,6-tetrahydropyridine-4-ylethynyl)pyridine LC-MS (APCI)m/z 185 (MH+). ¹H NMR (CDCl₃): δ8.59-8.55 (1 H, m); 7.64 (1 H, dt);7.43-7.39 (1 H, m); 7.20 (1 H, ddd); 6.30 (1H, bs); 3.51 (2H, q); 3.04(2 H, t); 2.37-2.31 (2 H, m).

[0343] 4-[(4-methylphenyl)ethynyl]-1,2,3,6-tetrahydropyridine LC-MS(APCI) mlz 198 (MH+). ¹H NMR (CDCl₃): δ8.91 (1 H, bs); 7.33 (2 H, d);7.15 (2 H, d); 6.06 (1 H, bs); 3.93-3.80 (2 H, m); 3.49-3.335 (2 H, m);2.73-2.60 (2 H, m); 2.37 (3 H, s).

[0344] 2-(Piperidin4-yloxy)-5-trifluoromethyl-pyridine Sodium hydride(0.52 g, 12 mmol, 55% in oil) was washed twice in hexane, and suspendedin dry dimethoxyethane (30 ml). 4-hydroxypiperidine (1.21 g, 12 mmol)and 2-chloro-5-trifluoromethylpyridine was dissolved in drydimethoxyethane (30 ml). The solution was added dropwise to the sodiumhydride-suspension. The reaction was stirred at 80° C. under nitrogenover night. After cooling. Water was carefully added to the mixture andthe solvents were removed by rotary evaporation. The residue wasdissolved in water and extracted with ethyl acetate. The organic phasewas dried over Na₂SO₄ and evaporated. The residue was chromatographed onsilica gel eluting with 80:20:2 EtOAc/MeOH/Et₃N affording 1.7 g (63%) ofthe title compound as a yellow oil, which crystallised after a fewhours. LC-MS (APCI) m/z 247.1 (MH+). ¹H NMR (CDCl₃): δ8.40 (1 H, s);7.74 (1 H, dd, J=2.52, 8.70 Hz); 6.78 (1 H, d, J=8.74 Hz); 5.25-5.17 (1H, m); 3.19-3.08 (2 H, m); 2.83-2.73 (2 H, m); 2.10-2.00 (2 H, m); 1.83(1 H., s); 1.73-1.62 (2 H, m).

[0345] The following amines were prepared in a similar way as descibeddescribed in the synthesis of2-(Piperidin-4-yloxy)-5-trifluoromethyl-pyridine.

[0346] 6-(Piperidin4-yloxy)-nicotinonitrile LC-MS (APCI) mn/z 204.2(MH+). ¹H NMR (CDCl₃): δ8.45 (1 H, s); 7.76 (1 H, dd, J=2.40, 8.77 Hz);6.78 (1 H, d, J=8.77 Hz); 5.28-5.17 (1H, m); 3.19-3.09 (2 H, m);2.83-2.74 (2 H,.m); 2.10-2.01 (2 H, m); 1.74-1.63 (2 H, m).

[0347] 5-Methyl-2-(piperidin4-yloxy)-pyridine ¹H NMR (Methanol-d4):δ7.90 (1 H, s); 7.46 (1 H, dd, J=2.47, 8.46 Hz); 6.68 (1H, d, J=8.50Hz); 5.07-4.98 (1 H, m); 3.15-3.07 (2 H, m); 2.82-2.73 (2 H, m); 2.23 (3H, s); 2.07-1.97 (2 H, m); 1.84-1.74 (2 H, m).

[0348] 2-Methoxy6-(piperidin4-yloxy)-pyridine ¹H NMR (CDCl₃): δ7.44 (1H,t, J=7.90 Hz); 7.25 (2 H, dd, J=1.83, 7.90 Hz); 5.19-5.11 (1 H, m); 3.82(3 H, s); 3.23-3.16 (2 H, m); 2.96-2.88 (2 H, m); 2.13-2.05 (2 H, m);1.89-1.79 (2H, m).

[0349] 2-chloro-6-(piperidine4-yloxy)-pyridine ¹H NMR (Methanol-d₄):δ7.64 (1 H, dd, J=7.60, 8.22 Hz); 6.96 (1 H, dd, J=0.66, 7.60 Hz); 6.73(1 H, dd, J=0.60, 8.19 Hz); 5.25-5.14 (1 H, m); 3.28-3.18 (2 H, m);3.05-2.94 (2 H, m); 2.19-2.07 (2 H, m); 1.93-1.80 (2 H, m).

[0350] 5-Fluoro-2-(piperidin4-yloxy)-pyrimidine ¹H NMR (CDCl₃): δ8.36 (2H, s); 5.16-5.06 (1 H, m); 3.29-3.18 (2 H, m); 2.98-2.87 (2 H, m);2.21-2.08 (2 H, m); 1.97-1.81 (2 H, m).

[0351] 2-(Piperidin4-yloxy)-4-trifluoromethyl-pyrimidine ¹H NMR (CDCl₃):δ8.75 (1 H, d, J=4.93 Hz); 7.27 (1 H, d, J=5.07 Hz); 5.39-5.30 (1 H, m);3.44-3.33 (2 H, m); 3.28-3.17 (2 H, m); 2.35-2.10 (4 H, m).

[0352] 5-Ethyl-2-(piperidin4-yloxy)-pyrimidine ¹H NMR (Methanol-d4):δ8.40 (2 H, s); 5.16-5.08 (1 H, m); 3.16-3.06 (2 H, m); 2.77-2.70 (2 H,m); 2.60 (2 H, q, J=7.66, 15.28 Hz); 2.10-2.00 (2 H, m); 1.76-1.66 (2 H,m); 1.23 (3 H, t, J=7.63 Hz).

[0353] 5-Methoxy-2-(piperidin4-yloxy)-pyridine; hydrochloride4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butylester (45 mg, 0.14 mmol) was dissolved in THF (3 ml) and conc. HCl (2ml) was added. The reaction was stirred at room temprature for 2 hrsafter which the solvents were removed in vacuo and the remaining waterwas removed by azeotropic evaporation using EtOH/Toulene affording 35 mg(97%) of the title compound as oily crystals. LC-MS (APCI) m/z 225.1(MH+).

[0354] The starting material was prepared as follows:

[0355] 2-Chloro-5-methoxy-2yridine 1-oxide 2-chloro-5-methoxy-pyridine(200 mg, 1.39 mmol) and mCPBA (360 mg, 2.09 mmol) was dissolved inCH₂Cl₂ (10 ml). The mixture was stiffed at room temperature for 2 days.The mixture was then diluted with CH₂Cl₂ and washed with 10% aqueousK₂CO₃ and brine and dried over Na₂SO₄. The solvent were removed in vacuoaffording 140 mg (63%) of the title compound as white crystals. ¹H NMR(DMSO-d₆): δ8.30 (1H, d, J=2.72 Hz); 7.68 (1 H, d, J=9.23 Hz); 7.08 (1H,. dd, J=2.70, 9.23 Hz); 3.31 (3 H, s).

[0356] 4-(5-Methoxy-1-oxy-pyridin-2-yloxy)-1-piperidine-1-carboxylicacid tert-butl ester Potassium tert-butoxide (128 mg, 1.14 mmol) wasdissolved in dry THF (10 ml) and 4-Hydroxy-piperidine-1-carboxylic acidtert-butyl ester (177 mg, 0.88 mmol) dissolved in dry THF (5 ml) wasadded under nitrogen. The mixture was stirred at room temperature for 10minutes after which 2-Chloro-5-methoxy-pyridine 1-oxide (140 mg, 0.88mmol) dissolved in dry THF (5 ml) was added. The reaction was stirredfor 3 days at room temperature. The solvent were removed and the residuewas partitioned between H₂O and CHCl₃. The organic phase was washed withbrine and dried over Na₂SO₄. The solvent were removed in vacuo affording245 mg (86%) of the title compound as a brown oil. ¹H NMR (CDCl₃):δ7.95-7.93 (1 H, m); 6.86-6.84 (2 H, m); 4.95-4.85 (1 H, m); 3.79 (3 H,s); 3.25-3.14 (2 H, m); 3.07-2.96 (2 H, m); 1.98-1.79 (4 H, m); 1.46 (9H, s).

[0357] 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester4-(5-Methoxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester (200 mg, 0.62 mmol) was dissolved in EtOH (5 ml).Indium (498 mg, 4.34 mmol) and saturated aqueous NH₄Cl (4 ml) was addedto the solution and the reaction was refluxed for 4 days. The mixturewas filtered through celite after cooling and the solvents were removedin vacuo. The residue was chromatographed on silica gel eluting with 5:1Heptane/EtOAc affording 50 mg (26%) of the title compound as a yellowishoil. ¹H NMR (CDCl₃): δ7.77 (1 H, d, J=3.06 Hz); 7.20 (1 H, dd, J=3.07,8.89 Hz); 6.66 (1 H, d, J=8.99 Hz); 5.14-5.07 (1 H, m); 3.80 (3 H. s);3.79-3.72 (2 H, m); 3.31-3.23 (2 H, m); 2.00-1.91 (2 H, m); 1.75-1.64 (2H, m); 1.47 (9 H, s).

[0358] 4-(4-Pyridin-3-yl-phenyl)piperazine; hydrochloride4-(4-Pyridin-3-yl-phenyl)piperazine-1-carboxylic acid tert-butyl ester(60 mg, 0.18 mmol) in THF (3 ml) and conc. HCl (3 ml) was stirred for 1hr. The solvents were removed in vacuo and the remaining water wasremoved by azeotropic evaporation using EtOH/Toulene, affording 50 mg(100%) of the title compound as a yellow powder. LC-MS (APCI) m/z 240.2(MH+).

[0359] The starting material was prepared as follows:

[0360] 4-(4-Iodophenyl)piperazine-1-carboxylic acid tert-butyl ester wasprepared according to La Clair in Angew. Chem. Int. Ed.1998, 37(3),325-329 in 55% overall yield starting from N-phenylpiperazine (19 mmol).

[0361] 4-(4-Pyridin-3-yl-phenyl)pilerazine-1-carboxylic acid tert-butylester (Ref Wellmar et al. J. Heterocycl. Chem. 32(4), 1995, 1159-1164.)4-(4-Iodophenyl)piperazine-1-carboxylic acid tert-butyl ester (0.272 g,0.70 mmoles), 3-pyridylboronic acid (0.078 g, 0.64 mmoles),tetrakis(triphenylphosphine)palladium (0.024 g, 0.02 mmoles), 1 M sodiumhydrogencarbonate (1.0 mL) and 1,2-dimethoxyethane (1.5 mL) were stirredunder nitrogen at 84° C. for 3 hours, taken up in ethyl acetate andwashed with water and brine. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated with silica (1 g) by rotaryevaporation to give a solid which was applied on a short silica column.Elution with dichloromethane, dichloromethane/ethyl acetate (4: 1) andneat ethyl acetate gave 0.060 g (32% yield) of the title compound as awhite solid and 0.060 g of starting material (the iodide), respectively.Yield was calculated from amount of converted iodide. LC-MS (APCI) m/z340.3 (MH+). ¹H NMR (Methanol-d4): δ8.75 (1H, d, J=2.0 Hz); 8.43 (1H,m); 8.04 (1H, m); 7.58 (2H, d, J=8.0 Hz); 7.47 (1H, m); 7.10 (2H,d,J=8.0 Hz); 3.59 (4H, m); 3.22 (4H, m); 1.50 (9H, s).

[0362] N-[3-(Piperidin-4-yloxy)-phenyl]-acetamide; hydrochloride4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.5mmol) was dissolved in dry CH₂Cl₂ and cooled to −10° C. Polymer boundtriphenylphosphie (750 mg, 2.25 mmol) was added and allowed to swell.N-(3-Hydroxy-phenyl)-acetamide (340 mg, 2.25 mmol) dissolved in dry THFwas added and the reaction was stirred at −10° C. for 10 minutes afterwhich DEAD (0.35 ml, 2.25 mmol) was added dropwise to the mixture. Thereaction was stirred over night allowing the temperature rise to roomtemperature. The polymer was filtered off, using a short plug of silicawith Toluene/EtOAc (5:1) as eluent. The volume of the combined fractionswas reduced by rotary evaporation and the solution was washed with 5%aqueous KOH and water, dried over Na₂SO₄ and the solvent removed invacuo. The resulting white powder was dissolved in THF (10 ml) and conc.HCl (10 ml) and stirred at ambient temperature for 1 hr. The solventswere removed in vacuo and the remaining water was removed by azeotropicevaporation using EtOH/Toulene, affording 230 mg (57%) of the titlecompound as a white powder. LC-MS (APCI) m/z 235.1 (MH+).

[0363] The following amines were prepared in a similar way as descibeddescribed in the synthesis N-[3-(Piperidin-4-yloxy)-phenyl]-acetamide.

[0364] 3-(Piperidin4-yloxy)-benzonitrile LC-MS (APCI) m/z 203.2 (MH+).

[0365] 4-(3-Methoxy-phenoxy)-piperidine LC-MS (APCI) m/z 208.2 (MH+).

[0366] 4-3-Trifluoromethoxy-phenoxy)-piperidine LC-MS (APCI) m/z 262.1(MH+).

[0367] 4-(2,4-Difluoro-phenoxy)-piperidine LC-MS (APCI) m/z 214.2 (MH+).

[0368] 4-(4-Chloro-phenoxy)-piperidine LC-MS (APCI) m/z 212.2 (MH+).

[0369] 4-(Piperidin4-yloxy)-benzonitrile LC-MS (APCI) m/z 203.2 (MH+).

[0370] 4-(4-Methoxy-phenoxy)-piperidine LC-MS (APCI) m/z 208.2 (MH+).

[0371] 4-(3,4-Dichloro-phenoxy)-piperidine LC-MS (APCI) m/z 246.1 (MH+).

[0372] 4-(3,4-Difluoro-phenoxy)-piperidine LC-MS (APCI) m/z 214.2 (MH+).

[0373] N-[4-(Piperidin4-yloxy)-phenyl]-acetamide LC-MS (APCI) m/z 235.1(MH+).

[0374] 4-{[(3,4-dimethylphenyl)methyl]oxy}piperidine hydrochloride LC-MS(APCI) m/z 220 (MH+).

[0375] 4-{[(2,5-dimethylphenyl)methyl]oxy}piperidine hydrochloride LC-MS(APCI) m/z 220 (MH+).

[0376] 5-chloro-2-piperidin4-ylpyridine hydrochloride Zn dust (225 mg,3.5 mmol) was stirred in THF (1 mL) under Ar and 1,2-dibromoethane (50μL) was added at room temperature. The mixture was heated to 65° C. for3 min and allowed to cool to room temperature before trimethylsilylchloride (70 μL) was added and the mixture was stirred at roomtemperature for 30 min. A solution of 4-iodo-N-Boc-piperideine (840 mg,2.7 mmol) in THF (1.5 mL) was slowly added and the reaction mixture wasstirred at 40° C. for 2 h. Pd₂(dba)₃ (22 mg, 0.024 mmol) and P(2-furyl)₃(23 mg, 0.10 mmol) were mixed in THF (0.5 mL), the mixture stirred atroom temperature for 10 min and then added to the organozink reagentsolution, followed by 2-bromo-5-chloro-pyridine (624 mg, 3.24 mmol) inTHF (1 mL) and DMA (4 mL). The reaction mixture was heated at 80° C. for3 h, allowed to cool to room temperature and then filtered throughCelite and diluted with EtOAc. The filtrate was washed with saturatedaqueous NaHCO₃ and brine, dried Na₂SO₄ and concentrated. Purification onSiO₂ eluting with heptane/EtOAc 95:5 to 2:1 gave tert-butyl4-(5-chloropyridin-2-yl)piperidine-1-carboxylate as an yellow oil (128mg, 16%). The oil was dissolved in THF (1.5 mL) and conc HCl (1.5 mL)and stirred at RT for 30 min. Concentration several times with tolueneand EtOH gave the title compound (89 mg, 89%) LC-MS (APCI) m/z 197(MH+). ¹H NMR (MeOD-d4): δ8.54 (1H, d); 7.86 (1 H, dd); 7.38 (1H, d);3.55-3-45 (2 H, m); 3.22-3.06 (3 H, m); 2.19-2.09 (2 H, m); 2.08-1.98 (2H, m).

[0377] 5-Benzyloxy-2-(piperidin4-yloxy)-pyridine; hydrochloride Theamine was prepared in the same way as described in the synthesis of5-Methoxy-2-(piperidin-4-yloxy)-pyridine. LC-MS (APCI) m/z 285 (MH+).

[0378] The starting material was prepared as follows:

[0379] 2-Chloro-5-benzyloxypyridine Sodium hydride (55% in oil, 236 mg,5.40 mmol) washed in Hexane and 2-Chloro-5-hydroxypyridine (350 mg, 2.70mmol) was suspended in dry DMF (20 ml). After 10 minutes at roomtemperature Benzylbromide (0.32 ml, 2.70 mmol) was added and the mixturewas stirred for an additional 2 hrs. The reaction was diluted with waterand extracted with EtOAc (3*50 ml). The combined organic layers werewashed with water and brine, and dried over Na₂SO₄. The solvent wasremoved by rotary evaporation, affording 520 mg (88%) of the titlecompound as a yellow oil. LC-MS (APCI) m/z 220 (MH+). ¹H NMR (CDCl₃):δ8.19 (1H, d, J=3.00 Hz); 7.55 (1H, dd, J=3.15, 8.81 Hz); 7.48-7.31 (6H,m); 5.19 (2H, s).

[0380] 2-Chloro-5-benzyloxy-pyridine 1-oxide The amine was prepared inthe same way as described in the synthesis of2-Chloro-5-methoxy-pyridine 1-oxide. LC-MS (APCI) m/z 236 (MH+). ¹H NMR(DMSO-d₆): δ8.38 (1H, d, J=2.61 Hz); 7.69 (1H, d, J=9.28 Hz); 7.47-7.33(5H, m); 7.15 (1H, dd, J=2.69, 9.15 Hz); 5.19 (2H, s).

[0381] 4-(5-Benzyloxy-1-oxy-peridin-2-yloxy)-piperidine-1-carboxylicacid tert-butyl ester The compound was prepared as described in thesynthesis of 4-(5-Methoxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylicacid tert-butyl ester. LC-MS (APCI) m/z 401 (MH+). ¹H NMR (DMSO-d₆):δ8.12 (1H, d, J=2.79 Hz); 7.48-7.32 (5H, m); 7.19 (1H, d, J=9.16 Hz);7.07 (1H, dd, J=2.88, 9.18 Hz); 5.13 (2H, s); 4.84-4.76 (1H, m);3.20-3.11 (2H, m); 3.00-2.87 (2H, m); 1.86-1.78 (2H, m); 1.59-1.49 (2H,m); 1.40 (9H, s).

[0382] 4-(5-Benzyloxy-pvridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester The compound was prepared as described in the synthesisof 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butylester. LC-MS (APCI) m/z 385 (MH+). ¹H NMR (CDCl₃): δ7.86 (1H, d, J=3.10Hz); 7.46-7.32 (5H, m); 7.28 (1H, dd, J=3.16, 9.04 Hz); 6.67 (1H, d,J=9.04 Hz); 5.16-5.08 (1H, m); 5.05 (2H, s); 3.84-3.72 (2H, m);3.33-3.25 (2H, m); 2.02-1.93 (2H, m); 1.76-1.66 (2H, m); 1.49 (9H, s).

[0383] 5-Hydroxy-2-(piperidin-4-yloxy)-pyridine trifluoroacetic acid4-(5-Benzyloxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester (476 mg, 1.19 mmol) was dissolved in Methanol (20 ml)and Pd(OH)₂ (30 mg) was added. The mixture was hydrogenated at 1 atm androom temperature for 24 hrs. The catalyst was filtered off, and themixture was purified using preparative HPLC affording, after freezedrying, 110 mg (30%) of the title compound as a TFA-salt and 34 mg (10%)of the neutral Boc-protected intermediate. LC-MS (APCI) m/z 195 (MH+).¹H NMR (DMSO-d₆): δ7.66 (1H, d, J=2.94 Hz); 7.20 (1H, dd, J=3.07, 8.82Hz); 6.68 (1H, d, J=8.93 Hz); 5.12-5.00 (1H, m); 3.29-3.00 (4H, m);2.16-2.02 (2H, m); 1.93-1.75 (2H, m).

[0384] 5-Bromo-2-(piperidin4-yloxy)-pyridine hydrochloride The amine wasprepared in the same way as described in the synthesis of5-Methoxy-2-(piperidin4-yloxy)-pyridine. LC-MS (APCI) m/z 257+259 (MH+)

[0385] The starting material was prepared as described in the synthesisof 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butylester:

[0386] 4-(5-Bromo-pyridin-2-yloxy)-piperidine-1-carboxylic acidtert-butyl ester LC-MS (APCI) m/z 357+359 (MH+). ¹H NMR (DMSO-d₆): δ8.26(1H, dd, J=0.53, 2.67 Hz); 7.88 (1H, dd, J=2.66, 8.81 Hz); 6.80 (1H, dd,J=0.53, 8.79 Hz); 5.15-5.07 (1H, m); 3.72-3.64 (2H, m); 3.20-3.09 (2H,m); 1.97-1.88 (2H, m); 1.58-1.48 (2H, m); 1.40 (9H, s).

[0387] 4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine hydrochloride4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-1-carbaldehyde (98 mg,0.34 mmol) was dissolved in MeOH (5 ml) and conc. HCl (12M, 5 ml) wasadded. The mixture was stirred at room temperature over night. Thesolvents were removed in vacuo and the remaining water was removed byazeotropic evaporation using EtOH/Toulene affording 102 mg (100%) of thetitle compound as a yellow powder. LC-MS (APCI) m/z 258 (MH+).

[0388] The starting material was prepared as follows:

[0389] 4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-1-carbaldehyde4-(5-Bromo-pyridine-2-yl)-piperazine-1-carbaldehyde (100 mg, 0.37 mmol),4-Fluorobenzeneboronic acid (55 mg, 0.39 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (10 mg,0.01 mmol), Toluene (2 ml), EtOH (0.5 ml) and 2M Na₂CO₃ solution (0.5ml, 1 mmol) were heated at 80° C. under N₂ overnight. After cooling themixture was diluted with toluene and separated. The organic phase waswashed with water and brine, filtered through a pad of celite and driedover Na₂SO₄. The solvent were removed in vacuo affording 100 mg (94%) ofthe title product as a beige powder. LC-MS (APCI) m/z 286 (MH+). ¹H NMR(DMSO-d₆): δ8.44 (1H, d, J=2.66 Hz); 8.10 (1H, s); 7.97 (1H, dd, J=2.52,8.82 Hz); 7.70-7.31 (2H, m); 7.31-7.21 (2H, m); 6.97 (1H, d, J=8.97 Hz);3.65-3.43 (8 H, m).

[0390] The following compounds were synthesised as described in thesynthesis of 4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazinehydrochloride:

[0391] 4-(5-(4-Methoxy-phenyl)-pyridine-2-yl)-piperazine hydrochlorideLC-MS (APCI) m/z 270 (MH+).

[0392] 4-(5-(4-Chloro-phenyl)-pyridine-2-yl)-piperazine hydrochlorideLC-MS (APCI) m/z 274, 276 (MH+).

[0393] 4-(5-(4-Trifluoromethoxy-phenyl)-pyridine-2-yl)-piperazinehydrochloride LC-MS (APCI) m/z 324 (MH+).

[0394] 4-(5-Furan-2-yl-pyridine-2-yl)-piperazine hydrochloride LC-MS(APCI) m/z 230 (MH+).

[0395] 4-(5-(1H-Pyrrol-2-yl)-pyridine-2-yl)-piperazine dihydrochlorideThe title compound was prepared from2-(6-(4-Formyl-piperazine-1-yl)-pyridine-3-yl)-pyrrole-1-carboxylic acidtert-butyl ester. LC-MS (APCI) m/z 229 (MH+).

[0396] 4-[3,3′]-Bipyridinyl-6-yl-piperazine hydrochloride LC-MS (APCI)m/z 241 (MH+).

[0397] 4-(6-Piperazine-1-yl-pyridine-3-yl)-benzonitrile hydrochlorideLC-MS (APCI) m/z 265 (MH+). HYDANTOINS OF FORMULA I HydantoinAnalysis⁽¹⁾

m/z 380 (MH+)

m/z 382 (MH+)

m/z 402/403 3:1 (MH+)

m/z 382 (MH+)

m/z 420 (MH+)

m/z 420 (MH+)

m/z 488 (MH+)

m/z 384/386 3:1 (MH+)

m/z 370 (MH+)

m/z 370 (MH+)

m/z 366 (MH+)

m/z 366 (MH+)

m/z 359 (MH+)

m/z 408 (MH+)

m/z 436 (MH+)

m/z 386/388 3:1 (MH+)

m/z 345 (MH+)

m/z 375 (MH+)

m/z 395 (MH+)

m/z 462 (MH+)

m/z 276 (MH+)

m/z 274 (MH+)

m/z 408 (MH+)

m/z 393 (MH+)

m/z 375 (MH+)

m/z 388 (MH+)

m/z 408 (MH+)

m/z 436 (MH+)

m/z 437 (MH+)

m/z 394 (MH+)

m/z 382 (MH+)

m/z 436 (MH+)

m/z 393 (MH+)

m/z 398 (MH+)

m/z 404 (MH+)

m/z 402 (MH+)

m/z 398 (MH+)

m/z 438 (MH+)

m/z 383 (MH+)

m/z 398 (MH+)

m/z 388 (MH+)

m/z 399 (MH+)

m/z 403 (MH+)

m/z 393 (MH+)

m/z 398 (MH+)

m/z 425 (MH+)

m/z 402 (MH+)

m/z 452 (MH+)

m/z 452 (MH+)

m/z 404 (MH+)

m/z 386 (MH+)

m/z 386 (MH+)

m/z 386 (MH+)

m/z 399 (MH+)

m/z 430 (MH+)

m/z 369 (MH+)

m/z 410 (MH+)

m/z 368 (MH+)

m/z 413 (MH+)

m/z 410 (MH+)

m/z 387 (MH+)

m/z 475 (MH+)

m/z 403 (MH+)

m/z 385 (MH+)

m/z 418 (MH+)

m/z 450 (MH+)

m/z 385 (MH+)

m/z 425 (MH+)

m/z 415 (MH+)

m/z 413 (MH+)

m/z 447, 449 (MH+)

m/z 448 (MH+)

m/z 460 (MH+)

m/z 464, 466 (MH+)

m/z 514 (MH+)

m/z 420 (MH+)

m/z 419 (MH+)

m/z 431 (MH+)

m/z 455 (MH+)

[0398] The following compounds were prepared in the same way as(5S)-5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione(Example 12) and purified either by precipitation and washing withEtOH/water or by preparative HPLC.

[0399](5S)-5-methyl-5-({[4-[4-(methyloxy)phenyl]-3.6-dihydropyridin-1(2l)-yl]sulfonyl}methyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 380 (MH+). ¹H NMR (Methanol-d₄): δ7.35 (2 H, d, J=8.9Hz); 6.87 (2 H, d, J=8.9 Hz); 6.01 (1 H, dd); 3.92 (2 H, dd); 3.78 (3 H,s); 3.56, 3.41 (1 H each, ABq, J=14.6 Hz); 3.51-3.46 (2 H, m); 2.62-2.57(2 H, m); 1.47 (3 H, s).

[0400](5S)-5-methyl-5-[({4-[4-(methyloxy)phenyl]piperidin-1-yl}sulfonyl)methyl]imidazolidine-2,4-dioneLC-MS (APCI) m/z 382 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H, s); 7.17 (2 H, d); 6.85 (2 H, d); 3.71 (3 H, s); 3.60 (2 H, dd); 3.50(1 H, part of ABq, J=14.8 Hz); 2.85 (2 H, q); 2.54 (1 H, t); 1.79 (2 H,d); 1.64-1.53 (2 H, m); 1.33 (3 H, s).

[0401](5S)-5-({[4-(4-chlorophenyl)4-hydroxypiperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 402/404 3:1 (MH+). ¹H NMR (DMSO-d₆): δ10.72 (1 H, s);8.01 (1 H, s); 7.51 (2 H, d); 7.37 (2 H, d); 5.22 (1 H, s); 3.49, 3.34(1 H each, ABq, J=14.9 Hz); 3.47-3.35 (2 H, m); 3.15 (2 H, q); 1.93 (2H, t); 1.64 (2 H, d); 1.33 (3 H, s).

[0402](5S)-5-methyl-5-[({4-[2-(methyloxy)phenyl]piperidin-1-yl}sulfonyl)methyl]imidazolidine-2,4-dioneLC-MS (APCI) m/z 382 (MH+). ¹H NMR (DMSO-d₆): δ10.72 (1 H, s); 8.01 (1H, s); 7.24-7.14 (2 H, m); 6.96 (1 H, d); 6.90 (1 H, t); 3.78 (3 H, s);3.60 (2 H, dd); 3.51, 3.33 (1 H each, ABq, J=14.7 Hz); 3.02-2.94 (1 H,m); 2.88 (2 H, q); 1.77 (2 H, d); 1.66-1.56 (2 H, m); 1.33 (3 H, s).

[0403](5S)-5-methyl-5-[({4-[4-(trifluoromethyl)phenyl]piperidin-1-yl}sulfonyl)methyl]imidazolidine-2.4-dioneLC-MS (APCI) m/z 420 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H, s); 7.66 (2 H, d); 7.50 (2 H, d); 3.63 (2 H, dd); 3.52, 3.34 (1Heach, ABq, J=14.9 Hz); 2.88 (2 H, ddd); 2.79-2.68 (1 H, m); 1.86 (2.H,d); 1.67 (2 H, ddd); 1.33 (3 H, s).

[0404](5S)-5-methyl-5-[({4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}sulfonyl)methyl]imidazoidine-2,4-dioneLC-MS (APCI) m/z 420 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.02 (1H, s); 7.63-7.52 (4 H, m); 3.63 (2 H, dd); 3.52 (1 H, part of ABq,J=14.9 Hz); 2.87 (2 H, ddd); 2.79-2.70 (1 H, m); 1.87 (2 H, d);1.75-1.63 (2 H, m); 1.33 (3 H, s).

[0405](5S)-5-[({4-[3,5-bis(trifluoromethyl)phenyl]piperidin-1-yl}sulfonyl)methyl]-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 488 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.02 (1H, s); 8.00 (2 H, s); 7.93 (1 H, s); 3.64 (2 H, dd); 3.52 (1 H, part ofABq, J=14.9 Hz); 2.95-2.81 (3 H, m); 1.89 (2 H, d); 1.83-1.69 (2 H, m);1.34 (3 H, s).

[0406](5S)-5-({[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 384/386 3:1 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s);8.03 (1 H, s); 7.47 (2 H, d); 7.40 (2 H, d); 6.23 (1 H, app s); 3.85 (2H, app s); 3.52, 3.39 (1 H each, ABq, J=14.7 Hz); 3.39-3.32 (2 H, m);2.55 (2 H, br s); 1.32 (3 H, s).

[0407](5S)-5-({[4-(3-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 370 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H, s); 7.38-7.31 (1 H, m); 7.15-7.08 (2 H, m); 7.05-6.98 (1H, m); 3.62(2 H, dd); 3.51, 3.33 (1 H each, ABq, J=14.7 Hz); 2.95-2.80 (2 H, m);2.68-2.60 (1 H, m); 1.82 (2 H, br d); 1.69-1.58 (2 H, m); 1.33 (3 H, s).

[0408](5S)-5-({[4-(2-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 370 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H, s); 7.36 (1 H, t); 7.30-7.20 (1 H, m); 7.18-7.12 (2 H, m); 3.63 (2 H,dd); 3.52, 3.33 (1 H each, ABq); 2.96-2.85 (3 H, m); 1.80 (2 H, brd);1.69 (2 H, ddd); 1.33.(3 H, s).

[0409](5S)-5-methyl-5-({[4-(4-methylphenyl)piperidin-1-yl]sulfonyl}methyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 366 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H,s); 7.15-7.07 (4 H, m); 3.60 (2 H, dd); 3.50, 3.32 (1 H each, ABq); 2.85(2 H, q); 2.59-2.51 (1 H, m); 2.25 (3 H, s); 1.79 (2 H, br d); 1.60 (2H, ddd).

[0410](5S)-5-methyl-5-({[4-(phenylmethyl)piperidin-1-yl]sulfonyl}methyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 366 (MH+). ¹H NMR (DMSO-d₆): δ10.70 (1 H, s); 7.96 (1H, s); 7.29-7.15 (5 H, m); 3.46 (2 H, t); 3.41, 3.24 (1H each, ABq,J=14.9 Hz); 2.68 (2 H, dt); 2.52 (2 H, d); 1.54-1.51 (3 H, m); 1.30 (3H, s).

[0411](5S)-5-[(1,4′-bipiperidin-1′-ylsulfonyl)methyl]-5-methylimidazolidine-2,4-dionetrifluoroacetic acid LC-MS (APCI) m/z 359 (MH+). ¹H NMR (DMSO-d₆):δ10.74 (1 H, s); 9.25 (1 H, br s); 8.02 (1 H, s); 3.63 (2 H, t); 3.51,3.34 (1 H each, ABq, J=14.8 Hz); 3.39 (2 H, d);.3.24 (1 H, t); 2.92 (2H, q); 2.81 (2 H, t); 2.07 (2 H, d); 1.82 (2 H, d); 1.74-1.58 (5 H, m);1.45-1.34 (1 H, m); 1.31 (3 H, s). ¹⁹F NMR (DMSO-d₆): δ-74.48.

[0412](5S)-5-({[4-(3-furan-2-yl-1H-pyrazol-5-yl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 408 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H, s); 7.66 (1 H, s); 6.64 (1H, s); 6.53 (1 H, s); 6.34 (1H, s);3.61-3.49 (2 H, m); 3.49 (1 H, half ABq, J=14.9 Hz); 2.94-2.84 (2 H, m);2.81-2.72 (1H, m); 1.98 (2 H, br d); 1.70-1.58 (2 H, m); 1.32 (3 H, s).

[0413](5S)-5-methyl-5-{[(4-{4-[(trifluoromethyl)oxy]phenyl}piperidin-1-yl)sulfonyl]methyl}imidazolidine-2,4-dioneLC-MS (APCI) m/z 436 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H, s); 7.40 (2 H, d); 7.28 (2 H, d); 3.70-3.55 (2 H, m); 3.51, 3.33 (1Heach, ABq, J=14.7 Hz); 2.94-2.80 (2 H, m); 2.73-2.61 (2 H, m); 1.86 (2H, d); 1.71-1.57 (2 H., m); 1.33 (3 H, s).

[0414](5S)-5-({[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 386/388 3:1 (MH+). ¹H NMR ([MSO-d₆): δ10.73 (1 H, s);8.01 (1 H, s); 7.36-7.28 (4 H, m); 3.66-3.54 (2 H, m); 3.51, 3.33 (1 Heach, ABq, J=14.9 Hz); 2.92-2.80 (2 H, m); 2.67-2.58 (1H, m); 1.81 (2 H,br d); 1.68-1.56 (2 H, m); 1.33 (3 H, s).

[0415](5S)-5-methyl-5-‡[(4-pyrrolidin-1-ylpiperidin-1-yl)sulfonyl]methyl}imidazolidine-2,4-dionetrifluoroacetic acid LC-MS (APCI) m/z 345 (MH+). ¹H NMR (DMSO-d₆):δ10.74 (1 H, s); 9.61 (1 H, br s); 8.01 (1 H, s); 3.60 (2 H, t); 3.51,3.36 (1 H each, ABq, J=14.8 Hz); 3.55-3.47 (2 H, m); 3.27-3.15 (1 H, m);3.13-3.02 (2 H, m); 2.80 (2 H, t); 2.12 (2 H, br d); 2.07-1.94 (2 H, m);1.86-1.77 (2 H, m); 1.62-1.49 (2 H, m); 1.32 (3 H, s). ¹⁹F NMR(DMSO-d₆): δ-74.02

[0416](5S)-5-methyl-5-({[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]sulfonyl}methyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 375 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.01 (1H, s); 4.65 (1 H, dd); 3.80-3.68 (2 H, m); 3.60-3.42 (3 H and water, m);3.33 (1H, half ABq, J=14.9 Hz); 3.19-3.00 (4 H, m); 2.09-1.92 (2 H, m);1.87-1.75 (2 H, m); 1.30 (3 H, s).

[0417]N-[1-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)piperidin-4-yl]benzamideLC-MS (APCI) m/z 395 (MH+). ¹H NMR (DMSO-d₆): δ10.72 (1 H, s); 8.30 (1H, d); 8.01 (1 H, s); 7.82 (2 H, d); 7.51 (1 H, t); 7.45 (2 H, t);3.96-3.85 (1 H, m); 3.52 (2 H, t); 3.50, 3.32 (1 H each, ABq, J=14.7Hz); 2.92 (2 H, t); 1.88 (2 H, d); 1.55 (2 H, q); 1.33 (3 H, s).

[0418](5S)-5-{[(4-{[2-(1,1-dimethylethyl)-1H-indol-5-yl]amino}piperidin-1-yl)sulfonyl]methyl}-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 462 (MH+). ¹H NMR (DMSO-d₆): δ10.72 (1 H, s); 10.37 (1H, s); 8.00 (1H, s); 7.02 (1H, d, J=8.4 Hz); 6.58 (1H, s); 6.45 (1 H, d,J=8.4 Hz); 5.86 (i H, s); 4.65 (1 H, Br s); 3.48, 3.29 (1 H each, ABq,J=14.7 Hz); 3.46 (2 H, t); 2.93 (2 H, t); 1.95 (2 H. t); 1.45-1.35 (2 H,m); 1.33 (3 H, s); 1.29(9 H, s).

[0419](5S)-5-methyl-5-[(Piperidin-1-ylsulfonyl)methyl]imidazolidine-2,4-dioneLC-MS (APCI) m/z 276 (MH+). ¹H NMR (DMSO-d₆): δ10.70 (1 H, s); 7.97 (1H, s); 3.44, 3.23 (1 H each, ABq, J=14.8 Hz); 3.13-3.01(4 H, m);1.58-1.42 (6 H, m); 1.30 (3 H, s).

[0420](5S)-5-[(3,6-dihydropyridin-1(2H)-ylsulfonyl)methyl]-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 274 (MH+). ¹H NMR (DMSO-d₆): δ10.72 (1 H, s); 8.00 (1H, s); 5.85-5.78 (1 H, m); 5.74-5.68 (1 H, m); 3.67-3.62 (2 H, m); 3.47,3.33 (1 H each, ABq, J=14.7 Hz); 3.22 (2 H, dd); 2.14-2.10 (2 H, m);1.31 (3 H, s).

[0421](5S)-5-methyl-5({[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]sulfonyl}methyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 408 (MH+). ¹H NMR (DMSO-d₆): δ10.86 (1 H, s); 10.75 (1H, s); 8.02 (1 H, s); 7.27-7.17 (1 H, m); 7.05-6.91 (3 H, m); 4.38-4.20(1 H, m); 3.65 (2 H, t); 3.56, 3.38 (1H each, ABq, J=14.8 Hz); 3.03-2.90(2¹H, m); 2.41-2.24 (2 H, m); 1.76 (2 H, d); 1.34 (3 H, s).

[0422](5S)-5-({[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 393 (MH+). ¹H NMR (DMSO-d₆): δ10.77 (1 H, s); 8.05.(1H, s); 8.05 (1 H, d); 7.93 (1 H, d); 7.56 (1 H, t); 7.41 (1 H, t);5.12-4.97 (1H, m); 3.71 (2 H, t); 3.58, 3.43 (1 H each, ABq, J=14.7 Hz);3.19-3.03 (2 H, m); 2.29-2.16 (4 H, m); 1.35 (3 H, s).

[0423](5S)-5-methyl-5-({[4-(pyridin-2-ylethynyl)-3,6-dihydropyridin-1(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dionetrifluoroacetic acid LC-MS (APCI) m/z 375 (MH+). ¹H NMR (DMSO-d₆):δ10.57 (1 H, s); 8.56 (1 H, d); 8.03 (1 H, s); 7.82 (1H, t); 7.53 (1H,d); 7.38 (1H, dd); 6.31 (1H, br s); 3.83 (2 H, d); 3.54, 3.41 (1 H each,ABq, J=14.8 Hz); 3.36-3.25 (2 H, m); 2.42-2.34 (2 H, m); 1.32 (3 H, s).¹⁹F NMR (DMSO-d₆): δ-75.10

[0424](5S)-5-methyl-5-({[4-[(4-methylphenyl)ethynyl]-3,6-dihydropyridin-1(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione LC-MS (APCI) nm/z 388 (MH+). ¹H NMR(DMSO-d₆): δ10.74 (1 H, s); 8.02 (1 H, s); 7.32 (2 H, d); 7.19 (2 H, d);6.17 (1 H, br s); 3.80 (2 H, d); 3.52, 3.39 (1 H each, ABq, J=14.8 Hz);3.29 (2 H, t); 2.39-2.32 (2 H, m); 2.30 (3 H, s); 1.32 (3 H, s).

[0425](5S)-5-({[4-(4-chlorophenyl)ethynyl]-3,6-dihydropyridin-1(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 408 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.02 (1H, s); 7.54-7.38 (4 H, m); 6.23 (1 H, br s); 3.87-3.76 (2 H, m); 3.53,3.41. (1 H each, ABq, J=14.9 Hz); 3.34-2.25 (2 H, m); 2.42-2.29 (2 H,m); 1.32 (3 H, s).

[0426](5S-5-[4-(3,4-Dichloro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z (APCI) m/z 436.1 (MH+). ¹H NMR (DMSO- d₆): δ10.74 (1 H,s); 8.01 (1 H, s); 7.53 (1 H, d, J=9.2 Hz); 7.31 (1 H, d, J=2.9 Hz);7.02 (1 H, dd, J=9.2, 2.9 Hz); 4.654.57 (1 H, m); 3.51, 3.34 (1 H each,ABq, J=15.2 Hz); 3.39-3.27 (2 H, m); 3.17-3.08 (2 H, m); 2.00-1.90 (2 H,m); 1.75-1.65 (2 H, m); 1.33(3 H, s).

[0427](5S)-5-[4-(5-(Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 403.3 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.20 (1H, d, J=2.7 Hz); 7.81 (1 H, dd, J=8.7, 2.7 Hz); 6.87 (1 H, d, J=2.7 Hz);5.16-5.03 (1H, m); 3.52, 3.35 (1H each, ABq, J=15.0 Hz); 3.43-3.28 (2 H,m); 3.19-3.07 (2 H, m); 2.08-1.95 (2 H, m); 1.80-1.65 (2 H, m); 1.33 (3H, s).(5S)-5-Methyl-5-[4-(5-trifluoromethyl-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-imidazolidine-2,4-dioneLC-MS (APCI) m/z 437 (MH+). ¹H NMR (CDCl₃): δ8.95 (1 H, s); 8.42-8.38 (1H, m); 7.79 (1 H, dd, J=8.8, 2.5 Hz); 6.81 (1 H, d, J=8.8 Hz); 6.71 (1H, s); 5.40-5.28 (1 H, m); 3.52-3.39 (2.H, m); 3.40-3.28 (2 H, m); 3.32(2 H, ABq, J=24.6, 14.0 Hz); 2.16-2.02 (2 H, m); 2.02-1.84 (2 H, m);1.67 (3 H, s).

[0428]6-[1-((4S)4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yloxy]-nicotinonitrileLC-MS (APCI) m/z 394.3 (MH+). ¹H NMR (DMSO- d₆): δ10.72 (1 H, s); 8.68(1 H, d, J=2.3 Hz); 8.14 (1 H, dd, J=8.7, 2.3 Hz); 8.00 (1 H, s); 6.98(1 H, d, J=8.7 Hz); 5.27-5.14 (1 H, m); 3.56-3.28 (4 H, m); 3.18-3.06 (2H, m); 2.08-1.96 (2 H, m); 1.81-1.66(2 H, m); 1.31 (3 H, s).

[0429](5S)-5-Methyl-5-(4-p-tolyloxy-piperidine-1-sulfonylmethyl)-imidazolidine-2,4-dioneLC-MS (APCI) m/z 382.5 (MH+). ¹H NMR (DMSO- d₆): δ10.73 (1 H, s); 8.01(1 H, s); 7.09 (2 H, d, J=8.4 Hz); 6.87 (2 H, d, J=8.4 Hz); 4.50-4.42 (1H, m); 3.50, 3.34 (1H each, ABq, J=14.8 Hz); 3.38-3.29 (2 H, m);3.17-3.09 (2 H, m); 2.23 (3 H, s); 1.99-1.89 (2 H, m); 1.73-1.63 (2 H,m); 1.33 (3 H, s).

[0430](5S)-5-Methyl-5-[4-(4-trifluoromethyl-phenoxy)-piperidine-1-sulfonylmethyl]-imidazolidine-2,4-dioneLC-MS (APCI) m/z 436.3 (MH+). ¹H NMR (DMSO- d₆): δ10.71 (1 H, brs); 8.02(1 H, s); 7.65 (2 H, d, J=8.8 Hz); 7.17 (2 H, d, J=8.8 Hz); 4.72-4.64 (1H, m); 3.52, 3.35 (1H each, ABq, J=14.7 Hz); 3.40-3.28 (2 H, m);3.19-3.10 (2 H, m); 2.05-1.95 (2 H, m); 1.78-1.68 (2 H, m); 1.33 (3 H,s).

[0431]4-[1-(4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yloxyl-benzonitrileLC-MS (APCI) M/Z 393.2 (MH+). ¹H NMR (DMSO- d₆): δ10.73 (1 H, s); 8.00(1 H, s); 7.76 (2 H, d, J=8.8 Hz); 7.15 (2 H, d, J=8.8 Hz); 4.74-4.65 (1H, m); 3.51, 3.34 (1 H each, ABq, J=14.9 Hz); 3.40-3.27 (2 H, m);3.17-3.07(2 H, m); 2.03-1.94(2 H, m); 1.77-1.66 (2 H, m); 1.32(3 H, s).

[0432](5S)-5-[4-(4-Methoxy-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 398.2 (MH+). ¹H NMR (DMSO- d₆): δ10.73 (1 H,. s); 8.01(1 H, s); 6.89 (4 H, ABq, J=29.1, 9.1 Hz); 4.43-4.34 (1 H, m); 3.70 (3H, m); 3.51, 3.33 (1 H, ABq, J=15.0 Hz); 3.38-3.28 (2 H, m); 3.16-3.05(2 H, m); 1.97-1.87 (2 H, m); 1.73-1.62 (2 H, m); 1.33 (3 H, s).

[0433] 5(5S)-5-[4-(3,4-Difluoro-phen(ox)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 404.2 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.01 (1H, s); 7.35 (1 H, q, J=19.6, 9.2 Hz); 7.19-7.11 (1 H, m); 6.86-6.80 (1H, m); 4.57-4.48 (1 H, m); 3.51, 3.34 (1 H each, ABq, J=14.9 Hz);3.38-3.28 (2 H. m); 2.16-2.06 (2 H, m); 2.00-1.90 (2 H, m); 1.74-1.64 (2H, m); 1.33 (3 H, s).

[0434](5S)-5-[4-(4-Chloro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 402 (MH+). ¹H NMR (DMSO- d₆): δ10.73 (1 H, s); 8.00 (1H, s); 7.32 (2 H, d, J=8.8 Hz); 7.00 (2 H, d, J=8.8 Hz); 4.56-4.48 (1 H,m); 3.50, 3.33 (1 H each, ABq, J=14.8 Hz); 3.37-3.28 (2 H, m);3.16-3.06(2 H, m); 2.00-1.90(2 H, m); 1.73-1.63 (2 H, m); 1.32(3 H, s).

[0435](5S)-5-4-(5-Ethyl-pyrimidin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 398 (MH+). ¹H NMR (DMSO- d₆): δ10.74 (1 H, s); 8.47 (2H, s); 8.02 (1 H, s); 5.11-5.03 (1 H, m); 3.52, 3.35 (1 H each, ABq,J=14.8 Hz); 3.42-3.28 (2 H, m); 3.19-3.10 (2 H. m); 2.54 (2 H, q,J=15.2, 7.6 Hz); 2.06-1.98 (2 H, m); 1.81-1.71 (2 H, m); 1.33 (3 H, s);1.17 (3 H, t, J=7.2 Hz).

[0436](5S)-5-Methyl-5-[4-(4-trifluoromethyl-pyrimidin-2-yloxy)-piperidine-1-sulfonylmethyl]-imidazolidine-2,4-dioneLC-MS (APCI) m/z 438 (MH+). ¹H NMR (CDCl₃): δ8.84-8.76 (1 H, m); 8.02 (1H, s); 7.31 (1 H, d, J=4.8 Hz); 6.33 (1 H, s); 5.41-5.34 (1 H, m);4.54-4.42 (4 H, m); 3.35, 3.24 (1 H each, ABq, J=12.9 Hz); 2.17-2.07 (4H, m); 2.02 (3 H, s).

[0437](5S)-5-Methyl-5-[4-(5-methyl-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-imidazolidine-2,4-dioneLC-MS (APCI) m/z 383 (MH+). ¹H NMR (CDCl₃): δ8.14 (1 H, s); 8.06-7.99 (2H, m); 7.19 (1H, s); 7.09 (1 H, d, J=1 1.6 Hz); 5.28-5.21 (1 H, m);3.70-3.41 (6 H, m); 2.44 (3 H, s); 2.13-1.96 (4 H, m); 1.62 (3 H, s).

[0438](5S)-5-[4-(4-Fluoro-benzoyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 398 (MH+). ¹H NMR (DMSO-d₆): δ8.06 (2 H, q, J=9.2, 6.0Hz); 7.40 (2 H, t, J=8.8 Hz); 3.61-3.41 (4 H, m); 3.00-2.91 (2 H, m);1.90-1.81 (2 H, m); 1.62-1.50 (2 H, m); 1.33 (3 H, s).

[0439](5S)-5-[4-(5-Fluoro-pyrimidin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 388 (MH+). ¹H NMR (CDCl1₃): δ8.42 (2 H, s); 8.30 (1 H,s); 6.40 (1 H, s); 5.30-5.23 (1 H, m); 3.53-3.35 (4 H, m); 3.36, 3.21 (1H each, ABq, J=14.4 Hz); 2.10-2.02 (4 H, m); 1.70 (3 H, s).

[0440](5S)-5-[4-(6-Methoxy-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 399 (MH+). ¹H NMR (MeOD): δ7.54 (1 H, t, J=8.4 Hz);6.33-6.28 (2 H, m); 5.24-5.14 (1H, m); 3.86 (3 H, s); 3.53-3.42 (2 H,m); 3.58, 3.39 (1 H each, ABq, J=14.4 Hz); 3.30-3.22 (2 H, m); 2.13-2.02(2 H, m); 1.96-1.82 (2 H, m); 1.47 (3 H, s).

[0441](5S)-5-[4-(6-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 403 (MH+). ¹H NMR (MeOD): δ7.65 (1 H, t, J=7.8 Hz);6.97 (1 H, d, J=7.2 Hz); 6.73 (1 H, d, J=7.2 Hz); 5.25-5.14 (1H, m);3.55-3.44 (2 H, m); 3.58, 3.39 (1 H each, ABq, J=14.4 Hz); 3.28-3.19(2H, m); 2.14-2.02 (2 H, m); 1.92-1.79 (2 H, m); 1.47 (3 H, s).

[0442]3-[1-(4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin4-yloxy]-benzonitrileLC-MS (APCI) m/z 393 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.02 (1H, s); 7.52-7.47 (2 H, m); 7.42-7.38 (1 H, m); 7.36-7.31 (1 H, m);4.694.61 (1 H, m); 3.52, 3.35 (1 H each, ABq, J=17.2 Hz); 3.18-3.07 (2H, m); 2.02-1.95 (2 H, m); 1.79-1.65 (2 H, m); 1.33 (3 H, s).

[0443](5S)-5-[4-(3-Methoxy-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) nm/z 398 (MH+). ¹H NMR (DMSO- d₆): δ10.74 (1 H, s); 8.01 (1H, s); 7.21-7.15 (1H, m); 6.58-6.50 (3 H, m); 4.57-4.49 (1H, m); 3.73 (3H, s); 3.51, 3.34 (1 H each, ABq, J=14.4 Hz); 3.17-3.08 (2 H, m);2.01-1.91 (2 H, m); 1.74-1.64 (2 H, m); 1.33 (3 H, s).

[0444]N-{4-[1(4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin4-yloxy]-phenyl}-acetamideLC-MS (APCI) m/z 425 (MH+). ¹H NMR (DMSO- d₆): δ10.69 (1 H, brs); 9.78(1 H, s); 8.00 (1 H, s); 7.47 (2 H, d, J=9.2 Hz); 6.91 (2 H, d, J=9.2Hz); 4.48-4.41 (1 H, m); 3.51 (1 H from ABq, J=14.4 Hz); 3.16-3.06 (2 H,m); 2.00 (3 H, s); 1.98-1.90 (2 H, m); 1.73-1.63 (2 H, m); 1.33 (3 H,s).

[0445](5S)-5-[4-(3-Chloro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 402 (MH+). 1H NMR (DMSO- d₆): δ10.76 (1 H, brs); 7.99(1 H, s); 7.31 (1 H, t, J=8.4 Hz); 7.08 (1 H, t, J=2.2 Hz); 7.02-6.95 (2H, m); 4.64-4.56 (1 H, m); 3.51 (1 H from ABq, J=14.4 Hz); 3.17-3.09 (2H, m); 2.00-1.91 (2 H, m); 1.75-1.65 (2 H, m); 1.33 (3 H, s).

[0446](5S)-5-Methyl-5-[4-(4-trifluoromethoxy-phenoxy)-piperidine-1-sulfonylmethyl]-imidazolidine-2,4-dioneLC-MS (APCI) m/z 452 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.01 (1H, s); 7.29 (2 H, d, J=8.8 Hz); 7.08 (2 H, d, J=9.2 Hz); 4.60-4.52 (1 H,m); 3.51 (1 H from ABq, J=14.8 Hz); 3.17-3.08 (2 H, m).; 2.02-1.93 (2 H,m); 1.75-1.65 (2 H, m); 1.33 (3 H, s).

[0447](5S)-5-Methyl-5-[4-(3-trifluoromethoxy-phenoxy)-piperidine-1-sulfonylmethyl]-imidazolidine-2,4-dioneLC-MS (APCI) m/z 452 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1 H, s); 8.01 (1H, s); 7.41 (1 H, t, J=8.4 Hz); 7.06-6.91 (3 H, m); 4.65-4.58 (1 H, m);3.51 (1 H from ABq, J=14.8 Hz); 3.18-3.08 (2 H, m); 2.02-1.93 (2 H, m);1.76-1.65 (2 H, m); 1.33 (3 H, s).

[0448](5S)-5-[4-(2,4-Difluoro-phenoxv)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 404 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1H, s); 8.02 (1H,s); 7.34-7.23 (2 H, m); 7.06-6.97 (1 H, m); 4.504.41 (1 H, m); 3.50 (1 Hfrom ABq); 3.17-3.06 (2 H, m); 2.02-1.90 (2 H, m); 1.78-1.65 (2 H, m);1.33 (3 H. s).

[0449](5S)-5-[4-(4-Fluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 386 (MH+). ¹H NMR (DMSO-d₆): δ10.75 (1 H, s); 8.02 (1H, s); 7.17-6.97 (2 H, m); 4.52-4.43 (1 H, m); 3.17-3.06 (2 H, m);2.00-1.89 (2 H, m); 1.75-1.62 (2 H, m); 1.33 (3 H, s).

[0450](5S)-5-[4-(3-Fluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 386 (MH+). ¹H NMR (DMSO-d₆): δ10.72 (1 H, s); 8.02 (1H, s); 7.36-7.26 (1 H, m); 6.91-6.71 (3 H, m); 4.62-4.52 (1 H, m);3.18-3.06 (2 H, m); 2.02-1.91 (2 H, m); 1.78-1.63 (2 H, m); 1.33 (3 H,s).

[0451](5S)-5-[4-(2-Fluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 386 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1H, s); 8.01 (1 H,s); 7.28-7.17 (2 H, m); 7.17-7.08 (1 H, m); 7.02-6.97 (1 H, m);4.59-4.47 (1 H, m); 2.04-1.92 (2 H, m); 1.80-1.67 (2 H, m); 1.33 (3 H,s).

[0452] (5S)-5-[4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 399 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1H, s); 8.01 (1H,s); 7.89 (1 H, d, J=3.16 Hz); 7.39 (1H, dd, J=3.18, 9.07 Hz); 6.77 (1 H,d, J=8.95 Hz); 5.08-4.96 (1 H, m); 3.76 (3 H, s); 3.51, 3.34 (1 H each,ABq, J=14.7 Hz); 3.43-3.29 (2 H, m); 3.18-3.05 (2 H, m); 2.05-1.94 (2 H,m); 1.77;1.61 (2 H, m); 1.33 (3 H, s).

[0453](5S)-5-Methyl-5-[4-(4-pyridin-3-yl-phenvl)-piperazine-1-sulfonylmethyl]-imidazolidine-2,4-dioneLC-MS (APCI) m/z 430 (MH+). ¹H NMR (DMSO-d₆): δ10.76 (1 H, s); 8.99 (1H, s); 8.60 (1 H, d, J=4.91 Hz); 8.35 (1 H, d, J=7.81 Hz); 8.04 (1 H,s); 7.70 (2 H, d, J=8.87 Hz); 7.12 (2 H, d, J=8.91 Hz); 3.57 (1 H fromABq); 3.35 (4 H, m); 3.27 (4 H, m); 1.33 (3 H, s).

[0454](5S)-5-methyl-5-({[4-(pyridin-2-yloxy)piperidin-1-yl]sulfonyl}methyl)imidazolidine-2,4-dioneLC-MS (APCI) m/z 369 (MH+). ¹H NMR (CDCl₃): δ1.73 (3H, s); 1.96-2.04(2H, m); 2.04-2.13 (2H, m); 3.21 (1H, d); 3.36-3.42 (3H, m); 3.45-3.50(2H, m); 5.29-5.33 (1H, m); 6.30 (1H, bs); 6.78 (1H, d); 6.93 (1H, t);7.65 (1H, t); 7.70 (1H, bs); 8.16 (1H, d).

[0455](5S)-5-[({4-[(3,4-dimethylbenzyl)oxy]piperidin-1-yl}sulfonyl)methl]-5-methylimidazolidine-2,4-dione (NB. contains 30% of the 2,3-dimethylisomer which was in the starting material) LC-MS (APCI) m/z 410 (MH+).¹H NMR (DMSO-d₆): δ1.3 (3H, s); 1.53-1.64 (2H, m); 1.83-1.89 (2H, m);2.18 (3H, s);

[0456] 2.20 (3H, s); 2.95-3.33 (2H, m); 3.25-3.31 (3H, m); 3.45 (1H, d);3.45-3.53 (1H, m); 4.42 (2H, s); 7.01-7.15 (3H, m); 7.97 (1H, s); 10.7O(1H, s).

[0457](5S)-5-methyl-5-{[(4-phenoxypiperidin-1-yl)sulfonyl]methyl}imidazolidine-2,4-dioneLC-MS (APCI) m/z 368 (MH+). 1H NMR (DMSO-d₆): δ1.30 (3H, s); 1.64-1.73(2H, m); 1.92-2.00 (2H, m); 3.08-3.15 (2H, m); 3.28-3.44 (4H, m);4.49-4.54 (1H, m); 6.92 (1H, t); 6.96 (2H, d); 7.28 (2H, t); 7.69 (1H,bs); 10.7 (1H, bs).

[0458]4-Fluoro-N-[1-((4S)-4-methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yl]-benzamideLC-MS (APCI) m/z 413 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1 H, s); 8.34 (1H, d, J=7.50 Hz); 8.02 (1 H, s); 7.94-7.88 (2 H, m); 7.33-7.26 (2 H, m);3.96-3.86 (1 H, m); 3.58-3.47 (2 H, m); 3.51, 3.32 (1 H each, ABq,J=14.81 Hz); 2.97-2.88 (2 H, m); 1.92-1.84 (2 H, m); 1.62-1.48 (2 H, m);1.33 (3 H, s).

[0459](5S)-5-[({4-[(2,5-dimethylbenzyl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 410 (MH+). ¹H NMR (DMSO-d₆): δ1.30 (3H, s); 1.54-1.62(2H, m); 1.85-1.91 (2H, m); 2.21 (3H, s); 2.24 (3H, s); 2.97-3.03 (2H,m); 3.27-3.34 (3H, m); 3.45 (1H, d); 3.49-3.55 (1H, m); 6.97-7.04 (2H,m); 7.11 (1H, s); 7.98 (1H, s); 10.70 (1H, s).

[0460](5S)-5-{[4-(5-chloropyridin-2-yl)piperidin-1-yl]sulfonyl}-5-methylimidazolidine-2,4-dioneLC-MS (APCI) m/z 387 (MH+). ¹H NMR (DMSO-d₆): δ10.72 (1 H, s); 8.54 (1H, d); 8.01 (1 H, s); 7.86 (1 H, dd); 7.38 (1 H, d); 3.61 (2 H, bt);3.50, 3.32 (1 H each, ABq, J=14.9 Hz); 2.96-2.76 (3 H, m); 1.92 (2 H,brd); 1.77-1.62 (2 H, m); 1.33 (3 H, s).

[0461](5S)-5-[4-(5-Benzyloxy-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 475 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1H, s); 8.01 (1H,s); 7.90 (1H, d, J=3.13 Hz); 7.48-7.30 (6H, m); 6.76 (1H, d, J=8.97 Hz);5.10 (2H, s); 5.05-4.98 (1H, m); 3.51 (1H (from ABq), J=14.84 Hz);3.40-3.30 (3H, m); 3.15-3.07 (2H, m); 2.07-1.95 (2H, m); 1.74-1.64 (2H,m); 1.33 (3H, s).

[0462](5S)-5-[4-(6-Chloro-pyridine-3-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 403 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1H, s); 8.17 (1H,d, J=3.10 Hz); 8.61 (1H, s); 7.56 (1H, dd, J=3.18, 8.80 Hz); 7.44 (1H,d, J=8.77 Hz); 4.67-4.59 (1H, m); 3.52, 3.35 (2H, ABq, J=15.22 Hz);3.39-3.28 (2H, m); 3.17-3.08 (2H, m); 2.03-1.93 (2H, m); 1.77-1.67 (2H,m); 1.33 (3H, s).

[0463](5S)-5-[4-(5-Hydroxy-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 385 (MH+). ¹H NMR (Methanol-d4): δ7.73 (1H, d, J=3.01Hz); 7.53 (1H, dd, J=3.11, 9.03 Hz); 7.04 (1H, d, J=9.04 Hz); 3.80-3.67(1H, m); 3.58, 3.41 (2H, ABq, J=15.04 Hz); 3.53-3.42 (2H, m); 3.36-3.18(2H, m); 2.17-2.02 (2H, m), 1.96-1.81 (2H, m); 1.48,(3H, s).

[0464](5S)-5-[4-(4-Chloro-phenylsulfanyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 418 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1H, s); 8.00 (1H,s); 7.45-7.39 (4H, m); 2.97-2.89 (2H, m); 2.00-1.91 (2H, m); 1.56-1.45(2H, m); 1.31 (3H, s).

[0465](5S)-5-[4-(4-Chloro-benzenesulfonyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 450 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1H, s); 7.99 (1H,s); 7.86 (2H, d, JF8.77 Hz); 7.77 (2H, d, J=8.75 Hz); 3.66-3.54 (2H, m);3.50-3.41 (1H, m); 3.44, 3.32 (1H each, ABq, J=14.63 Hz); 2.82-2.73 (2H,m); 1.97-1.88 (2H, m); 1.57-1.42 (2H, m); 1.30 (3H, s).

[0466](5S)-5-[4-(4-Fluoro-phenylamino)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 385 (MH+). ¹H NMR (Methanol-d4): δ7.20-7.11 (4H, m);3.84-3.71 (2H, m); 3.60-3.48 (1H, m); 3.56, 3.39 (1H each, ABq, J=14.96Hz); 2.97-2.84 (2H, m); 2.10-2.00 (2H, m); 1.69-1.53 (2H, m); 1.46 (3H,s).

[0467] N-{3-[1-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yloxy]-phenyl}-acetamideLC-MS (APCI) m/z 425 (MH+). ¹H NMR (DMSO-d₆): δ10.74 (1H, s); 9.89 (1H,s); 8.01 (1H, s); 7.37-7.33 (1H, m); 7.21-7.14 (1H, m); 7.08-7.03 (1H,m); 6.65 (1H, dd, J=1.89, 8.04 Hz); 4.49-4.42 (1H, m); 3.51, 3.34 (1Heach, ABq,J=14.73 Hz); 3.39-3.28 (2H, m); 3.18-3.08(2H, m); 2.02 (3H,s); 2.00-1.92 (2H, m); 1.76-1.65 (2H, m); 1.33 (3H, s).

[0468](5S)-5-[4-(4-Chloro-benzoyl)-piperazine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 415 (MH+). ¹H NMR (DMSO-d₆): δ10.75 (1H, s); 8.04 (1H,s); 7.54 (2H, d, J=8.38 Hz); 7.45 (2H, d, J=8.38 Hz); 3.79-3.55 (2H,bs); 3.56, 3.35 (1H each, ABq, J=14.84 Hz); 3.51-3.31 (2H, bs);3.27-3.06 (4H, bs); 1.33 (3H, s).

[0469]1-((4S)-4-Methyl-2,5-dioxo-imidazolidine-4-ylmethanesulfonyl)-piperidine4-carboxylicacid (4-fluoro-phenyl)-amide LC-MS (APCI) m/z 413 (MH+). ¹H NMR(DMSO-d₆): δ10.74 (1H, s); 9.97 (1H, s); 8.02 (1H, s); 7.65-7.58 (2H,m); 7.16-7.09 (2H, m); 3.62-3.52 (2H, m); 3.49,3.33 (1H each, ABq,J=14.94 Hz); 2.87-2.77 (2H, m); 2.48-2.39 (1H, m); 1.91-1.84 (2H, m);1.70-1.57 (2H, m); i.33 (3H, s).

[0470] (5S)-5-[4-(5-Bromo-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 447, 449 (MH+). ¹H NMR (DMSO-d₆): δ10.73 (1H, s); 8.28(1H, d, J=2.64Hz); 8.01 (1H, s); 7.91 (1H, dd, J=2.60, 8.84 Hz); 6.83(1H, d, J=8.79 Hz); 5.12-5.05 (1H, m); 3.52, 3.35 (1H each, ABq, J=14.85Hz); 3.41-3.34 (2H, m); 3.17-3.08 (2H, m); 2.06-1.97 (2H, m); 1.78-1.67(2H, m); 1.33 (3H, s).

[0471](5S)-5-[4-(5-(4-Fluoro-phenyl)-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 448 (MH+). ¹H NMR (DMSO-d₆): δ10.75 (1H, s); 8.45 (1H,d, J=2.51 Hz); 8.02 (1H, s); 7.88 (1H, dd, J=2.57, 8.86 Hz); 7.70-7.62(2H, m); 7.30-7.22 (2H, m); 6.98 (1H, d, J=8.94 Hz); 3.70-3.62 (4H, m);3.55, 3.36 (1H each, ABq, J=14.73 Hz); 3.26-3.19 (4H, m); 1.32 (3H, s)

[0472](5S)-5-[4-(5-(4-Methoxy-phenyl)-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 460 (MH+).

[0473](5S)-5-[4-(5-(4-Chloro-phenyl)-pyridin-2-yl)-pierazine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 464, 466 (MH+).

[0474](5S)-5-[4-(5-(4-Trifluoromethoxy-phenyl)-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 514 (MH+).

[0475](5S)-5-[4-(5-Furan-2-yl-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 420 (MH+).

[0476](5S)-5-Methyl-5-(4-[5-(1H-pyrrol-2-yl)-pyridine-2-yl]-piperazine-1-sulfonylmethyl)-imidazolidine-2,4-dioneLC-MS (APCI) m/z 419 (MH+).

[0477](5S)-5-(4-[3,3′]-Bipyridinyl-6yl-piperazine-1-sulfonylmethyl)-5-methyl-imidazolidine-2,4-dioneLC-MS (APCI) m/z 431 (MH+).

[0478](4S)-4-(6-[4-(4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonvi)-piperazine-1-yl]-pyridine-3-yl)-benzonitrileLC-MS (APCI) m/z 455 (MH+).

EXAMPLE 14

[0479] Compounds with the general formula

[0480] were synthesised according to the method described in Example 12.R R2 Analysis

m/z 543 (MH+)⁽¹⁾

m/z 562 (MH+)⁽¹⁾

m/z 511 (MH+)⁽¹⁾

m/z 523 (MH+)⁽¹⁾

m/z 443 (MH+)⁽¹⁾

[0481]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3,4,4trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dioneThe title compound was prepared as described in Example 12 from racemic{2,5-dioxo-4-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidin-4-yl}methanesulfonylchloride and 5-chloro-2-(piperidin-4-yloxy)-pyridine. LC-MS (APCI) m/z543 (MH+). ¹H NMR (DMSO-d₆): δ1.28 (6H, s); 1.63-1.74 (2H, m); 1.95-2.05(2H, m); 2.77 (3H, s); 3.14 (4H, d); 3.53-3.73 (3H, m); 4.14 (1H, q);5.04-5.11 (1H, m); 6.85 (1H, d); 7.80 (1H, dd); 7.94 (1H, s); 8.19 (1H,d); 10.83 (1H, s).

[0482] The startingmaterial was prepared as follows:

[0483]3-[3-(benzylthio)-2-oxopropyl]-1,5,5-trimethylimidazolidine-2,4-dioneBenzyl mercaptan (256 μl, 2.2 mmol) was stirred with cesium carbonate(712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at room temperature for1 hour. 3-(3-bromo-2-oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione(552 mg, 1.99 mmol) prepared as in WO99/06361 was added and the mixturestirred 18 hours at room temperature. The reaction mixture was treatedwith water, extracted into ethyl acetate (3×25 ml), the organic phasescombined, brine washed and dried. The product was purified by silicachromatography, eluting with 50% ethyl acetate/iso-hexane to give 300 mgproduct. LC-MS (APCI) m/z 321 (MH+). ¹H NMR (CDCl1₃): δ1.45 (6H, s);2.91 (3H, s); 3.16 (2H, s); 3.70 (2H, s); 4.53 (2H, s); 7.22-7.33 (5H,m).

[0484]5-[(benzylthio)methyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-ylmethyl]imidazolidine-2,4-dioneThe title compound was prepared as described in the synthesis of5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione inExample 12. LC-MS (APCI) m/z 391 (MH+). ¹H NMR (DMSO-d₆): δ1.28 (6H, s);2.64 and 2.76 (2H, abq, J=14.2 Hz); 2.78 (3H, s); 3.54 & 3.64 (2H, abq,J=14.2 Hz); 3.73 (2H, s); 7.20-7.32 (5H, m); 7.98 (1H, s); 10.83 (1H,s).

[0485]{2,5-dioxo-4-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidin-4-yl}methanesulfonylchloride The title compound was prepared as described in the synthesisof [(4S) and (4R)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonylchloride in Example 12. ¹H NMR (CD₃OD): δ1.38 (6H, s); 2.89 (3H, s);3.81 and 3.92 (2H, abq, J=14.3 Hz); 4.61 (2H, s).

[0486] The following compounds were prepared as described in thesynthesis of5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dione.

[0487]5-[({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dioneLC-MS (APCI) m/z 562 (MH+). ¹H NMR (DMSO-d₆): δ1.26 (6H, s); 2.76 (3H,s); 3.16-3.22 (4H, m); 3.48-3.76 (8 H, m); 7.02 (1H, d); 7.81-7.76 (2H,m); 8.43 (1H, s); 10.83 (1H, s).

[0488]5-[4-(4-Fluoro-phenyl-piperazine-1-sulfonylmethyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dioneLC-MS (APCI) m/z 511 (MH+). ¹H NMR (DMSO-d₆): δ1.28 (6H, s); 2.77 (3H,s); 3.10-3.16 (4H, m); 3.21-3.26 (4H, m); 3.48-3.71 (4H, m); 6.95-7.09(4H, m); 7.88 (1H, s); 10.84 (1H, bs).

[0489]5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-{2-[(phenylmethyl)oxy]ethyl}imidazolidine-2,4-dioneThe title compound was prepared as described in the synthesis of5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dionestarting from 5-Chloro-2-(piperidine-4-yloxy)-pyridine hydrochloride and(2,5-dioxo4-{2-[(phenylmethyl)oxy]ethyl}imidazolidin-4-yl)methanesulfonylchloride. LC-MS (APCI) m/z 523 (MH+). ¹HNMR (DMSO-d₆): δ1.37-1.79 (3H,m); 1.83-2.08 (4H, m); 3.00-3.56 (7H, m partially obscured by D₂O);4.33-4.44 (2H, m); 5.01-5.12 (1H, m); 6.85 (1H, d); 7.21-7.36 (5H, m),7.80 (1H, dd); 8.02 (1H, s); 8.19 (1H, d); 10.70 (1H, bs).

[0490]6-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1,3-diazaspiro[4.5]decane-2,4-dione LC-MS (APCI) m/z 443 (MH+).

[0491] The startingmaterial was prepared as follows:

[0492] 6-[(phenylmethyl)thio]-1,3-diazaspiro [4.5]decane-2,4-dioneBenzylmercaptan (937 mg, 7.5 mmol) was dissolved in 70 mL of THF. NaH(362 mg 60%, 9.0 mmol) was added and the slurry was stirred for someminutes. 2-chlorocyclohexanone (1.0 g, 7.5 mmol) was added and thereaction was stirred at rt over night. The solid was filtered of and thesolvent was removed by rotary evaporation. Potassium cyanid (4 eq),(NH₄)₂CO₃ (8 eq) and 25 mL of ethanol was added. The reaction wasstirred in a sealed vial at 80° C. over night. The suspension wasfiltered and the solid was recrystallised from DMSO and water to givethe title compound as a white solid LC-MS (APCI) m/z 291 (MH+). ¹H NMR(DMSO-d₆): δ1.21-1.81 (8 H, m); 2.79 (1H, dd); 3.67-3.76 (2H, m);7.18-7.32 (5H, m); 8.43 (1H, s); 10.68 (1H, s).

EXAMPLE 15

[0493]

[0494]5-Methyl-5-(1-(toluene4-sulfonyl)-cyclopentyl)-imidazolidine-2,4-dione1-(1-(Toluene-4-sulfonyl)-cyclopentyl))-ethanone (0.10 g, 0.38 mmol),potassium cyanide (0.049 g, 0.75 mmol), ammonium carbonate (0.18 g, 1.9mmol), 50% ethanol in water (1.6 mL) were stirred in a sealed tube (2 mLvolume) at 90° C. for 70 hours. The solution was acidified with 10%acetic acid to pH 6 and concentrated by rotary evaporation to half ofits original volume upon which part of the product fell out. Thesolution and its solid contents were taken up in ethyl acetate, theaqueous phase was separated and washed twice with ethyl acetate. Thecombined organic phases were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated by rotary evaporation to give0.74 g of a white solid. The crude product was dissolved in methanol (5mL), concentrated with silica (1 g) by rotary evaporation and applied ona short silica column. Elution with ethyl acetate/n-heptane (1:2 and2:1) gave 0.060 g (48%) of the title product as colourless needles.LC-MS (APCI) m/z 337 (MH+). ¹H NMR (DMSO-d₆): δ0.96-1.10 (1H, m);1.32-1.44 (1H, m); 1.36 (3H, s); 1.47-1.58 (2H, m); 2.10-2.30 (4H, m);2.40 (3H, s); 7.41 (2H, d, J=8 Hz); 7.72 (2H, d, J=8 Hz); 7.80 (1H, bs)and 10.7 (1H, bs). ¹³C NMR (DMSO-d₆): δ21.0, 22.60, 22.64, 26.1, 26.3,30.8, 31.5, 64.1, 78.9, 129.2, 130.3, 135.3, 144.2, 156.0 and 176.2.

[0495] The starting material was prepared as follows:

[0496] 1-(Toluene-4-sulfonyl)-propan-2-one was prepared according toCrandall et al. J. Org. Chem. 1985, (8 ) 50, 1327-1329 from sodiump-toluensulfinate dihydrate (4.2 g, 18 mmol), chloroacetone (1.0 mL, 12mmol), n-tetrabutylammonium bromide (0.30 g) and water-benzene-acetone4:3:3 (10 mL). Work-up and chromatography on silica of the crude usingethyl acetate/ n-heptane (1:3 through 1:2) as eluent gave 2.4 g (95%) ofthe title product as an oil which crystallised on standing in thefridge. LC-MS (APCI) mz 213 (MH+). ¹H NMR (CDCl₃): δ2.38 (3H, s); 2.42(3H, s); 4.10 (2H, s); 7.35 (d2H, d, J=8 Hz); 7.74 (d, 2H, d, J=8 Hz).¹³C NMR (CDCl₃): δ21.7, 31.4, 67.7, 128.0, 129.8, 135.5, 145.3 and195.9.

[0497] 1-(1-(Toluene-4-sulfonyl)-cyclopentyl))-ethanone1-(Toluene-4-sulfonyl)-propan-2-one (0.10 g, 0.47 nmmol),1,4-diiodobutane (0.068 mL, 0.52 mmol), finely ground potassiumcarbonate (0.14 g, 1.0 mmol) and dry dimethylsulfoxide (0.80 mL) werestirred at 50° C. (oil bath temperature) for 22 hours. The heating wasshut off and stirring was continued at 22° C. for 22 hours. The crudeproduct was taken up in ethyl acetate, washed with water (5×50 mL) andbrine (1×50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated by rotary evaporation. The oily residue was chromatographedon silica using ethyl acetate/n-heptane (1:4 through 1:3) to give 0.10 g(80%) of the title product as a colourless oil. LC-MS (APCI) m/z 267(MH+). ¹H NMR (CDCl₃): δ1.52 (2H, m); 1.77 (2H, m); 2.26 (2H, m); 2.37(2H, m); 2.42 (3H, s); 2.48 (3H, s); 7.30 (2H, d, J=8 Hz) and 7.60 (2H,d, J=8 Hz). ¹³C NMR (CDCl1₃): δ21.7, 25.4, 28.0, 31.3, 83.9, 129.4,129.5, 133.2, 145.0 and 202.5.

What we claim is:
 1. A compound of the formula I or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof

wherein X is selected from NR1, O, S; Y1 and Y2 are independentlyselected from O, S; Z is selected from SO, SO₂; m is 1 or 2; A isselected from a direct bond, (C1-6)alkyl, (C1-6)haloalkyl, or(C1-6)heteroalkyl containing a hetero group selected from N, O, S, SO,SO2 or containing two hetero groups selected from N, O, S, SO, SO2 andseparated by at least two carbon atoms; R1 is selected from H,(C1-3)alkyl, haloalkyl; Each R2 and R3 is independently selected from H,halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl,heteroalkyl-heteroaryl, aryl-alkyl, aryl-heteroalkyl, heteroaryl-alkyl,heteroaryl-heteroalkyl,aryl-aryl, aryl-heteroaryl, heteroaryl-aryl,heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl,alkyl-cycloalkyl, alkyl-heterocycloalkyl; Each R4 is independentlyselected from H, halogen, (C1-3)alkyl or haloalkyl; Each of the R2 andR3 radicals may be independently optionally substituted with one or moregroups selected from alkyl, heteroalkyl, aryl, heteroaryl, halo,haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, arylthiol,alkylsulfon, haloalkylsulfon, arylsulfon, aminosulfon,N-alkylaminosulfon, N,N-dialkylaminosulfon, arylaminosulfon, amino,N-alkylamino, N,N-dialkylamino, amido, N-alkylamido, N,N-dialkylamido,cyano, sulfonamino, alkylsulfonamino, arylsulfonamino, amidino,N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguanidino,2-nitro-ethene-1,1-diamin, carboxy, alkyl-carboxy, nitro, carbamate;Optionally R2 and R3 may join to form a ring comprising up to 7 ringatoms, or R2 and R4 may join to form a ring comprising up to 7 ringatoms, or R3 and R4 may join to form a ring comprising up to 7 ringatoms; R5 is a monocyclic, bicyclic or tricyclic group comprising one,two or three ring structures each of up to 7 ring atorns independentlyselected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, witheach ring structure being independently optionally substituted by one ormore substituents independently selected from halogen, hydroxy, alkyl,alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino,alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol,alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate,alkylcarboxylate, aminocarboxy, N-alkylamino-carboxy,N,N-dialkylamino-carboxy, wherein any alkyl radical within anysubstituent may itself be optionally substituted with one or more groupsselected from halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino,N,N-dialkylamino, N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro,thiol, alkylthiol, alkylsulfonyl, N-alkylaminosulfonyl, carboxylate,alkylcarboxy, aminocarboxy, N-alkylaminocarboxy,N,N-dialkylaminocarboxy, carbamate; when R5 is a bicyclic or tricyclicgroup, each ring structure is joined to the next ring structure by adirect bond, by —O—, by (C1-6)alkyl, by (C1-6)haloalkyl, by(C1-6)heteroalkyl, by (C1-6)alkenyl, by (C1-6)alkynyl, by sulfone, byCO, by NCO, by CON, by NH, by S, by C(OH) or is fused to the next ringstructure
 2. A compound of the formula I as claimed in claim 1 or apharmaceutically acceptable salt or an in vivo hydrolysable esterthereof, wherein X is NR1, Z is SO₂ or SO, at least one of Y1 and Y2 isO, m is 1, and R1 is H, (C1-3) alkyl, or (C1-3) haloalkyl.
 3. A compoundof the formula I as claimed in either claim 1 or claim 2 or apharmaceutically acceptable salt or an in vivo hydrolysable esterthereof, wherein R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl,alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl,alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl.
 4. Acompound of the formula I as claimed in any of the preceding claims or apharmaceutically acceptable salt or an in vivo hydrolysable esterthereof, wherein each of R3 and R4 is independently selected from H,methyl.
 5. A compound of the formula I as claimed in any of thepreceding claims or a pharmaceutically acceptable salt or an in vivohydrolysable ester thereof, wherein R5 comprises one, two or threeoptionally substituted aryl or heteroaryl 5 or 6 membered rings.
 6. Acompound of the formula I as claimed in any of the preceding claims or apharmaceutically acceptable salt or an in vivo hydrolysable esterthereof, wherein R5 is a bicyclic or tricyclic group comprising two orthree optionally substituted ring structures.
 7. A compound of theformula II or a pharmaceutically acceptable salt or an in vivohydrolysable ester thereof

wherein each of G1, G2 and G4 is a monocyclic ring structure comprisingeach of up to 7 ring atoms independently selected from cycloalkyl, aryl,heterocycloalkyl or heteroaryl, with each ring structure beingindependently optionally substituted by one or two substituentsindependently selected from halogen, hydroxy, haloalkoxy, amino,N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkylsulfone, haloalkyl sulfone, alkylcarbamate, alkylamide, wherein anyalkyl radical within any substituent may itself be optionallysubstituted with one or more groups selected from halogen, hydroxy,amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy,aryloxy, heteroaryloxy, carbamate; Z is SO₂; each of B and F isindependently selected from a direct bond, O, (C1-6)alkyl,(C1-6)heteroalkyl, alkynyl, CO, NCO, CON, NH, S; R2 is selected from H,alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl,(N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkylcycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl,alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl,alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; R3 and R4are independently selected from H or (C1-3)alkyl; Optionally R2 and R3may join to form a ring comprising up to 7 ring atoms, or R2 and R4 mayjoin to form a ring comprising up to 7 ring atoms, or R3 and R4 may jointo form a ring comprising up to 7 ring atoms.
 8. A compound of theformula II as claimed in claim 7 or a pharmaceutically acceptable saltor an in vivo hydrolysable ester thereof, wherein R2 is alkyl,aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl orheteroaryl-alkyl.
 9. A compound of the formula Ia or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof

wherein each of G1 and G2 is a monocyclic ring structure comprising eachof up to 7 ring atoms independently selected from cycloalkyl, aryl,heterocycloalkyl or heteroaryl, with each ring structure beingindependently optionally substituted by one or two substituentsindependently selected from halogen, hydroxy, haloalkoxy, amino,N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkylsulfone, haloalkyl sulfone, alkylcarbamate, alkylamide, wherein anyalkyl radical within any substituent may itself be optionallysubstituted with one or more groups selected from halogen, hydroxy,amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy,aryloxy, heteroaryloxy, carbamate; Z is S0₂; B is selected from a directbond, O, (C1-6)alkyl, (C1-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl; R2is selected from H, (C1-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl,thioalkyl, or R2 is a group of formula III

C and D are independently selected from a direct bond, H, (C1-C6)alkyl,(C1-C6)haloalkyl, or (C1-C6)heteroalkyl containing one or two heteroatoms selected from N, O or S such that when two hetero atoms arepresent they are separated by at least two carbon atoms; G3 is amonocyclic ring structure comprising up to 7 ring atoms independentlyselected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl,optionally substituted by one or two substituents independently selectedfrom halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano,nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, or alkylsubstituted with one or more groups selected from halogen, hydroxy,amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy;Optionally R2 is substituted with halo, haloalkyl, hydrbxy, alkoxy,haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino,(N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone,aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido,N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino,amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino,thioguanidino, 2-nitroguanidino, carboxy, alkylcarboxy, carbamate; R3and R4 are independently selected from H or (C1-3)alkyl; Optionally R2and R3 may join to form a ring comprising up to 7 ring atoms, or R2 andR4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4may join to form a ring comprising up to 7 ring atoms.
 10. A compound ofthe formula hIa as claimed in claim 9 or a pharmaceutically acceptablesalt or an in vivo hydrolysable ester thereof, wherein B is selectedfrom a direct bond, O, CO, S, alkynyl.
 11. A compound of the formula IIaas claimed in either claim 9 or claim 10 or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof, wherein R2 isselected from H, (C1-6)alkyl, aryl-(C1-6)alkyl or heteroaryl-(C1-6)alkyloptionally substituted with halo, haloalkyl, hydroxy, alkoxy,haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino,(N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone,aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido,N-alkylamido, N,N-dialkylamido, carbamate, cyano, sulfonamino,alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino,N-cyano-guanidino, thioguanidino, 2-nitroguanidino,2-nitro-ethene-1,1-diamino, carboxy, alkylcarboxy, carbamate.
 12. Acompound of the formula IIa as claimed in any of claims 9 to 11 or apharmaceutically acceptable salt or an in vivo hydrolysable esterthereof, wherein each of R3 and R4 is H.
 13. A compound of the formulaIIb or a pharmaceutically acceptable salt or an in vivo hydrolysableester thereof

wherein G1 is a monocyclic ring structure comprising each of up to 7ring atoms independently selected from cycloalkyl, aryl,heterocycloalkyl or heteroaryl, with each ring structure beingindependently optionally substituted by one or two substituentsindependently selected from halogen, hydroxy, haloalkoxy, amino,N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy,. alkylsulfone, haloalkyl sulfone, alkylcarbamate, alkylamide, wherein anyalkyl radical within any substituent may itself be optionallysubstituted with one or more groups selected from halogen, hydroxy,amino, N-alkylamino, N,N-dialkylarnino, cyano, nitro, alkoxy,haloalkoxy, aryloxy, heteroaryloxy, carbamate; G2 is optionallysubstituted piperidine or piperazine; B is selected from a direct bond,O, (C1-6)alkyl, (C1-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl; R2 isselected from H, (C1-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl,thioalkyl, or R2 is a group of formula III

C and D are independently selected from a direct bond, H, (C1-C6)alkyl,(C1-C6)haloalkyl, or (C1-C6)heteroalkyl containing one or two heteroatoms selected from N, O or S such that when two hetero atoms arepresent they are separated by at least two carbon atoms; G3 is amonocyclic ring structure comprising up to 7 ring atoms independentlyselected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl,optionally substituted by one or two substituents independently selectedfrom halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano,nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, or alkylsubstituted with one or more groups selected from halogen, hydroxy,amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy;Optionally R2 is substituted with halo, haloalkyl, hydroxy, alkoxy,haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino,(N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone,aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido,N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino,amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino,thioguanidino, 2-nitroguanidino, carboxy, alkylcarboxy, carbamate; R3and R4 are independently selected from H or (C1-3)alkyl; Optionally R2and R3 may join to form a ring comprising up to 7 ring atoms, or R2 andR4 may join to form a ring comprising up to 7 ring atoms, or R3 and R4may join to form a ring comprising up to 7 ring atoms.
 14. Apharmaceutical composition which comprises a compound of the formula Ias claimed in claim or a compound of the formula II as claimed in claim7 or a compound of the formula Ia as claimed in claim 9 or a compound ofthe formula IIb as claimed in claim 13 or a pharmaceutically acceptablesalt or an in vivo hydrolysable ester thereof and a pharmaceuticallyacceptable carrier.
 15. A method of treating a metalloproteinasemediated disease or condition which comprises administering to awarm-blooded animal a therapeutically effective amount of a compound ofthe formulae I or II or IIa or IIb or a pharmaceutically acceptable saltor in vivo hydrolysable ester thereof.
 16. Use of a compound of theformulae I or II or IIa or IIb or a pharmaceutically acceptable salt orin vivo hydrolysable precursor thereof in the preparation of amedicament for use in the treatment of a disease or condition mediatedby one or more metalloproteinase enzymes.